JP2016516059A - 治療用ペプチド - Google Patents
治療用ペプチド Download PDFInfo
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- JP2016516059A JP2016516059A JP2016503067A JP2016503067A JP2016516059A JP 2016516059 A JP2016516059 A JP 2016516059A JP 2016503067 A JP2016503067 A JP 2016503067A JP 2016503067 A JP2016503067 A JP 2016503067A JP 2016516059 A JP2016516059 A JP 2016516059A
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Abstract
Description
本出願は、米国特許仮出願番号第61/792,034号(2013年3月15日出願)および米国特許仮出願番号第61/913,198号(2013年12月6日出願)の利益を主張するものであり、これらの出願のそれぞれのすべては、それら全体において参照により本明細書に取り込まれる。
本発明は、米国国立衛生研究所助成金番号第P01 AI045757号および第P01 CA78378号の下、政府により支援を受けた。政府は本発明において一定の権利を有する。
本発明は、ヒトを対象とする治療用組成物(例えば、ペプチド)に関する。
一部の例では、本明細書に記載の治療用組成物は、疾患または状態に関連する結合パートナー(例えば、免疫原(複数可)、抗原(複数可)、および/またはエピトープ(複数可))と相互作用(例えば、結合、特異的結合、および/または免疫特異的結合)することができ、治療用組成物および結合パートナー間の相互作用により、状態または疾患に対し正の免疫応答が生じる(例えば、対象において疾患または症状の程度が軽減する)。
表1
** 配列は、1、2、3、4、5、5未満、または10未満で保存的なアミノ酸の改変を含有し得る。
# 配列は、記載の配列、例えば、FR1、FR2、FR3、および/またはFR4の相当する領域内に対し(例えば、少なくとも)80%、85%、90%、95%、96%、97%、98%、99%、および/または100%配列同一性を有し、並びに/あるいはCDR 1、2、および/または3の相当する領域内に1、2、3、4、5、5未満、または10未満で保存的なアミノ酸の改変を有する、配列または変異体を含む。
## 配列は、記載の配列に対し(例えば、少なくとも)80%、85%、90%、95%、96%、97%、98%、99%、および/または100%配列同一性を有する配列または変異体を含み、配列は対応するアミノ酸(AA)をコードする。
AA#は、VHまたはVLアミノ酸配列を示す。
核酸##は、VHまたはVL核酸配列を示す。
一部の例では、本開示は、本開示のペプチド(例えば、表1に開示される)に相当する(例えば、本開示のペプチドをコードする)ヌクレオチド配列を提供する。これらの配列には、本開示のペプチドに関係するすべての縮重配列を包含し、すなわち、特定のペプチドおよび変異体並びにその誘導体を1つコードする配列を有するすべての核酸を包含する。したがって、具体的な各核酸配列は記載されないものの、各配列およびすべての配列は、実際のところ本開示のポリペプチド配列により本明細書に開示されかつ記載される。
一部の例では、本願発明は、MICAに免疫特異的に結合するペプチドおよび細胞内T細胞受容体シグナル伝達ドメインを含むキメラ抗原受容体(CAR)を提供する。(Kalos M、et al.、Sci Transl Med. 2011 Aug 10;3(95))。一部の態様では、CARは、MICAに免疫特異的に結合するペプチド、細胞外ヒンジドメイン、T細胞受容体膜貫通ドメイン、および細胞内T細胞受容体シグナル伝達ドメインを含む。本願発明のさらなる態様は、本願発明のCARに関連する、関連核酸、組換え発現ベクター、宿主細胞、細胞集団、抗体またはその抗原結合部分、および医薬組成物を提供する。
一部の例では、本明細書で開示される治療用組成物には、癌の処置に使用される他の化合物、薬剤、および/または剤を含有させることができる。このような化合物、薬剤、および/または剤としては、例えば、化学療法剤、低分子抗癌剤または所定の癌に対する免疫応答を刺激する抗体を挙げることができる。一部の例では、治療用組成物には、例えば、本明細書で開示される1つ以上のペプチド、および1つ以上の抗CTLA−4抗体若しくはペプチド、抗PD−1抗体若しくはペプチド、抗PDL−1抗体若しくはペプチド、抗OX40(CD134、TNFRSF4、ACT35および/またはTXGP1Lとしても知られている)抗体若しくはペプチド、抗GITR(TNFRSF18、AITRおよび/またはCD357としても知られている)抗体若しくはペプチド、抗LAG−3抗体若しくはペプチド、および/または抗TIM−3抗体若しくはペプチドが挙げられる。例えば、一部の例では、本明細書で開示される治療用組成物は、1つ以上(例えば、1、2、3、4、5、または10未満)の化合物と組み合わせることができる。
一部の例では、方法には、状態または疾患を有するまたは有したヒト対象、および状態または疾患に対し正の免疫応答を示すまたは示したヒト対象を選別することが包含され得る。一部の例では、好適な対象には、例えば、状態または疾患を有するまたは有していたものの、疾患またはそれらの病態から回復している対象、現在では疾患の症状が(例えば、同様の状態または疾患を有する他の対象(例えば、大多数の対象)と比較して)軽減している対象、並びに/あるいは、例えば、無症候期(例えば、同様の状態または疾患を有する他の対象(例えば、大多数の対象)と比較して)において、状態または疾患を有するまたは有していたものの、状態または疾患を有しつつ(例えば、同様の状態または疾患を有する他の対象(例えば、大多数の対象)と比較して)より長期間生存している対象、が包含される。一部の例では、状態または疾患に対してワクチンを接種している(例えば、ワクチン接種歴があるおよび/またはワクチンを接種されたことがあるおよびワクチンを再接種されている(例えば、免疫補助剤入りワクチンを接種されている))対象を選別することができる。
一部の例では、本開示は、本明細書で開示される組成物を対象に投与することを包含する処置方法を提供する。
以下にさらに詳細に記載される通り、TTCFは大腸菌(Eschericia coli)において発現させ、BirA酵素による部位特異的モノビオチン化のためBirA部位をN末端に取り付けた。タンパク質とビオチン化部位の間に可動性リンカーを配置し、抗体の結合に関係する立体障害を回避した。TTCFは、アニオン交換クロマトグラフィーにより精製し、BirAによりビオチン化し、ゲル濾過クロマトグラフィーにより、未結合のビオチンおよびBirAから分離した。蛍光標識したストレプトアビジンを、モル比1:4でビオチン化TTCF抗原とインキュベートし、TTCF四量体を生成した。これらの四量体を、次に一連のmAbとともに使用して、破傷風トキソイドに特異的な記憶B細胞を同定した。
Franz et al.,Blood,118(2):348〜357(2011)に記載の通りに方法を実施した。細胞は、BD FACS Aria II細胞選別機で分取した。細胞は単一細胞として分取した。サンプルからは、最初に、一連の除外マーカー(CD3、CD14、CD16、7AAD)が陰性のCD19+細胞をゲーティングし、次に、CD27を高発現しかつCD19を即時的に(immediate level)発現していると同定された形質芽球をゲーティングし、最後に四量体+ CD19+細胞をゲーティングした。
TAATACGACTCACTATAGGTTCGGGGAAGTAGTCCTTGACCAGG(配列番号:19);
TAATACGACTCACTATAGGGATAGAAGTTATTCAGCAGGCACAC(配列番号:20);
TAATACGACTCACTATAGGCGTCAGGCTCAGRTAGCTGCTGGCCGC(配列番号:21)。
TTCF四量体および単量体を比較した。Alexa−488によりTTCFを蛍光標識し、次に単量体形態で使用するか、あるいは未標識のストレプトアビジンを使用して四量体に変換した(上記を参照されたい)。次に、濃縮B細胞を、同濃度のTTCF−Alexa−488四量体または単量体とインキュベートした。対照タンパク質(CD80膜近位ドメイン)を同様の方法で標識し、同様に四量体として使用した。
オーバーラップPCRにより、IgG重鎖およびκ鎖の定常部を、単離された可変配列と連結して、完全ヒト型抗体を生成した。CHO−S細胞を使用し、無血清哺乳類発現系により、6〜8日間にわたって抗体を一過性に発現させた。プロテインGおよびゲル濾過クロマトグラフィーを使用して、抗体を精製した。
本明細書に記載の方法を使用して、MICAに対し免疫特異的に結合する抗体を作製した。
mRNAの増幅
IgG−T7:AATACGACTCACTATAGGTTCGGGGAAGTAGTCCTTGACCAGG(配列番号:22)
κ−T7:TAATACGACTCACTATAGGGATAGAAGTTATTCAGCAGGCACAC(配列番号:23)
λ−T7:TAATACGACTCACTATAGGCGTCAGGCTCAGRTAGCTGCTGGCCGC(配列番号:24)
VHL−1:TCACCATGGACTG(C/G)ACCTGGA(配列番号:25)
VHL−2:CCATGGACACACTTTG(C/T)TCCAC(配列番号:26)
VHL−3:TCACCATGGAGTTTGGGCTGAGC(配列番号:27)
VHL−4:AGAACATGAAACA(C/T)CTGTGGTTCTT(配列番号:28)
VHL−5:ATGGGGTCAACCGCCATCCT(配列番号:29)
VHL−6:ACAATGTCTGTCTCCTTCCTCAT(配列番号:30)
VkL−1:GCTCAGCTCCTGGGGCTCCTG(配列番号:31)
VkL−2:CTGGGGCTGCTAATGCTCTGG(配列番号:32)
VkL−3:TTCCTCCTGCTACTCTGGCTC(配列番号:33)
VkL−4:CAGACCCAGGTCTTCATTTCT(配列番号:34)
VlL−1:CCTCTCCTCCTCACCCTCCT(配列番号:35)
VlL−2:CTCCTCACTCAGGGCACA(配列番号:36)
VlL−3:ATGGCCTGGA(T/C)C(C/G)CTCTCC(配列番号:37)
CgII:GCCAGGGGGAAGAC(C/G)GATG(配列番号:38)
CkII:TTTCAACTGCTCATCAGATGGCGG(配列番号:39)
ClII:AGCTCCTCAGAGGAGGG(C/T)GG(配列番号:40)
VH−1:CAGGT(G/C)CAGCTGGT(G/A)CAGTC(配列番号:41)
VH−2:CAG(A/G)TCACCTTGAAGGAGTC(配列番号:42)
VH−3:(G/C)AGGTGCAGCTGGTGGAGTC(配列番号:43)
VH−4:CAGGTGCAGCTGCAGGAGTC(配列番号:44)
VH−5:GA(G/A)GTGCAGCTGGTGCAGTC(配列番号:45)
VH−6:CAGGTACAGCTGCAGCAGTC(配列番号:46)
Vk−1:CG(A/C)CATCC(A/G)G(A/T)TGACCCAGT(配列番号:47)
Vk−2:CGAT(A/G)TTGTGATGAC(C/T)CAG(配列番号:48)
Vk−3:CGAAAT(T/A)GTG(T/A)TGAC(G/A)CAGTCT(配列番号:49)
Vk−4:CGACATCGTGATGACCCAGT(配列番号:50)
Vl−1:CCAGTCTGTGCTGACTCAGC(配列番号:51)
Vl−2:CCAGTCTGCCCTGACTCAGC(配列番号:52)
Vl−3:CTCCTATGAGCTGAC(T/A)CAGC(配列番号:53)
CgIII:GAC(C/G)GATGGGCCCTTGGTGGA(配列番号:54)
CkIII:AAGATGAAGACAGATGGTGC(配列番号:55)
ClIII:GGGAACAGAGTGACCG(配列番号:56)
第1回目のPCR
VHL1−58:TCACTATGGACTGGATTTGGA(配列番号:57)
VHL2−5:CCATGGACA(C/T)ACTTTG(C/T)TCCAC(配列番号:58)
VHL3−7:GTAGGAGACATGCAAATAGGGCC(配列番号:59)
VHL3−11:AACAAAGCTATGACATATAGATC(配列番号:60)
VHL3−13.1:ATGGAGTTGGGGCTGAGCTGGGTT(配列番号:61)
VHL3−13.2:AGTTGTTAAATGTTTATCGCAGA(配列番号:62)
VHL3−23:AGGTAATTCATGGAGAAATAGAA(配列番号:63)
VHL4−39:AGAACATGAAGCA(C/T)CTGTGGTTCTT(配列番号:64)
VHL4−61:ATGGACTGGACCTGGAGCATC(配列番号:65)
VHL−9:CCTCTGCTGATGAAAACCAGCCC(配列番号:66)
VH1−3/18:CAGGT(C/T)CAGCT(T/G)GTGCAGTC(配列番号:67)
VH1−45/58:CA(A/G)ATGCAGCTGGTGCAGTC(配列番号:68)
VH2−5:CAG(A/G)TCACCTTGA(A/G)GGAGTCTGGT(配列番号:69)
VH3−9/23/43:GA(A/G)GTGCAGCTG(T/G)TGGAGTC(配列番号:70)
VH3−16:GAGGTACAACTGGTGGAGTC(配列番号:71)
VH3−47:GAGGATCAGCTGGTGGAGTC(配列番号:72)
V4−34:CAGGTGCAGCTACAGCAGTG(配列番号:73)
V4−30−2/39:CAGCTGCAGCTGCAGGAGTC(配列番号:74)
VH7−4−1:CAGGTGCAGCTGGTGCAATC(配列番号:75)
本明細書に記載の方法を使用して、生物学的特性と臨床的な相関を有するさらなる抗MICA抗体を開発した。癌の細胞ワクチン(GM−CSF形質導入された癌細胞、GVAXとして参照)と、T細胞上のCTLA−4受容体に対するイピリムマブ(YERVOY(商標)(Bristol Myers Squibから入手可能))による阻害を遮断する抗体との接種を受けた患者において、共通の対立遺伝子産物と反応するMICA特異的抗体を同定した。次に、MICA四量体を使用して、血清MICAの反応が最も高かった患者の末梢血単核細胞からB細胞を単離した。実施例5において概説する通り、単一細胞PCRにより、これらのB細胞から、重鎖および軽鎖配列を決定した。この試行により、北アメリカの人口集団において共通する対立遺伝子産物を認識する抗体を同定した。
フローサイトメトリーにより、単離した抗MICA抗体CM24002 Ab2の自己腫瘍細胞への結合能を評価した(図27)。患者CM24002から骨髄を得て、CM24002 Ab2により、腫瘍細胞への結合を試験した。次に、骨髄試料から、CD33+ CD34+細胞として腫瘍細胞を同定した。次に、腫瘍細胞を、10μg/mLの、抗MICA抗体CM24002 Ab2、陽性対照の市販のMICA抗体(BioLegend)、または陰性対照抗体(TTCF特異性)により染色した。図27に示す通り、CM24002 Ab2はこれらの細胞に強力に結合した。CM24002 Ab2は非腫瘍細胞(CD16+およびCD3+細胞)に対し結合を示さず、バックグラウンドの結合のみがCD14+細胞にみられたことから、抗腫瘍特異性が実証された(データ不掲載)。
単離された抗MICA抗体CM24002 Ab2が、同族受容体であるNKG2Dによる可溶性MICA介在性の下方制御を妨げる能力を評価した。患者由来の血清CM24002を1:10希釈して使用して、ヒトNK細胞とともに48時間インキュベートした。これらの培養物に、CM24002 Ab2(濃度10μg/mL)、市販の陽性対照MICA抗体(BioLegend)または陰性対照抗体(TTCF特異的)を加えた。48時間の時点で、NKG2Dの発現をフローサイトメトリーにより評価した(図28)。患者由来の血清CM24002は、NKG2Dの発現を強力に下方制御した(したがって、この受容体の機能を不能にした)。CM24002 Ab2および陽性対照MICA抗体は、NK細胞によるNKG2Dの細胞表面での発現を部分的に回復した。特異性を実証するために、患者の血清の代わりに組換えMICA 2ng/mLとともに細胞をインキュベートして、上記の実験を繰り返した(図29)。CM24002 Ab2はNKG2D発現のMICA介在性の下方制御を完全に妨げたのに対し、陰性対照抗体(TTCF特異的)は効果を有さなかった(図29)。これらのデータは、ヒトNK細胞上の重要なNKG2D受容体の阻害は、ヒトMICA抗体により妨げられることを実証する。
CM24002 Ab2が細胞介在性細胞傷害を可能にするか評価するため、10μg/mLのCM24002 Ab2、陰性対照抗体(TTCF特異的)、または陽性対照抗体(BioLegend)の存在下で、ヒトNK細胞(エフェクター細胞)を、組換えMICA(2ng/mL)とともに48時間インキュベートした。48時間後、細胞を洗浄し、エフェクター:標的比20:1、10:1、および5:1で、K562腫瘍細胞とともに4時間インキュベートした。NK細胞による標的細胞の特異的な溶解は、K562腫瘍細胞からの細胞質タンパク質(LDH)の放出により測定した。MICA抗体の非存在下においては、NK細胞によるK562腫瘍細胞の殺傷は観察されなかった。しかしながら、CM24002 Ab2は、NK細胞介在性のK562腫瘍細胞の溶解を非常に促進させ、かつすべてのエフェクター:標的比において、マウスMICAの陽性対照抗体よりも効果的であった(図30)。(Fc受容体によりというよりは)NKG2D経路によりK562腫瘍細胞の殺傷が実際に介在されることがさらに実証された。さらに2つの実験群(NKG2DおよびヒトFcブロック用の遮断抗体による)を加え、上記の実験を繰り返した。加えて、CM33322 Ab29も試験した。データから、CM24002 Ab2およびCM33322 Ab29を加えることで、NK細胞介在性細胞傷害が可能になることが示される。NKG2D遮断抗体を加えた場合にはK562細胞の殺傷は生じなかったのに対し、Fc遮断試薬の場合にはわずかに効果が示された(図31)。これらのデータは、CM24002 Ab2およびCM33322 Ab29がNKG2D経路の抗腫瘍機能を回復させることを示す。
NKG2D受容体は、MICAのα1およびα2ドメイン頂部に結合するため、同じ部位に結合する抗体は、NKG2D受容体と競合し、NK細胞による腫瘍細胞の殺傷を妨げる可能性がある。α3ドメインに結合する抗体は、NKG2D受容体の結合を遮断できないため、特に対象となる。同時に、このような抗体は、タンパク質分解による腫瘍細胞表面からのMICAの切断に干渉し得る。MICA α3ドメインに対する抗MICA抗体の性能を、前述の細胞数測定ビーズアッセイにより評価した。ビオチン化組換えタンパク質をストレプトアビジンビーズ上に捕捉した。次に、ビーズを、10μg/mLの抗体CM24002 Ab2、CM24002 Ab4、CM33322 Ab11、CM33322 AB29、陰性対照の抗体(TTCF特異的)、または陽性対照の抗体(BioLegend)とともにインキュベートし、続いてFITCにより標識した抗ヒトIgG二次抗体とともにインキュベートし、ビーズに結合したFITC蛍光をフローサイトメトリーにより定量した(図32)。図32に示す通り、CM33322 Ab29はMICA α3ドメインに結合するため、治療応用に関し非常に興味を引く。
広範な癌を標的とした際のCM24002 Ab2およびCM33322 Ab29の使用可能性を評価した。CM24002 Ab2およびCM33322 Ab29による標識性について、多発性骨髄腫(RPMI 8226およびXg−1)、卵巣癌(OVCAR3)、急性骨髄性白血病(U937)、黒色腫(K028)、肺癌(1792および827)、および乳癌(MCF7)細胞をひと通り試験した。1% BSAを添加したPBSに、腫瘍細胞を1×106個/mLの濃度で再懸濁し、10μg/mLの、CM24002 Ab2およびCM33322 Ab29、並びに陽性および陰性対照(それぞれマウスMICA抗体およびTTCF−特異的抗体)(直接的に結合させたもの)により4℃で1時間染色した。フローサイトメトリーにより標識を評価した(図33)。試験した細胞株の大部分に関し、CM24002 Ab2およびCM33322 Ab29は、いずれも、市販の陽性対照により標識した場合と比較してより良好に各腫瘍細胞型に結合した。
市販のLuminexアッセイを用い、CM33322 Ab29の対立遺伝子産物特異性を評価した。市販の試験キットは、単一のサンプルにおいて結合性を評価することを可能にする、それぞれ固有の蛍光特性を有するLuminexビーズに直接結合した組換えMICA対立遺伝子産物(MICA*001、*002、*007、*012、*017、*018、*027、*004、*009、および*015)を含有する。記載のMICA対立遺伝子産物によりコーティングしたLuminexビーズを、10μg/mLの、CM33322 Ab29、BioLegend陽性対照、および陰性対照(TTCF)とともに1時間インキュベートし、続いて、PEを結合させた抗ヒトIgG二次抗体とともにインキュベートした。記載の抗体とともに60分間インキュベートし、続いてPE結合抗ヒト二次抗体とともにインキュベートした後、装置Luminex 200を用い蛍光を測定した(図34)。CM33322 Ab29が市販のアッセイに存在するすべての対立遺伝子産物に結合し得たことから、この抗体はMICAの遺伝子型とは関係なく患者に使用できることが示唆された。
腫瘍増殖に対する抗MICA抗体の影響を直接的に試験するために、マウスB16を使用して抗MICA抗体のインビトロおよびインビボ生物学的活性を評価した。この試験のために、B16マウス黒色腫細胞を、ヒトMICAを発現するように形質導入した。フローサイトメトリーを、MICAの細胞B16表面発現を検出するために使用した(図44)。
腫瘍細胞から分離するMICAを減少させるCM24002 Ab2およびCM33322 Ab29の可能性を試験した。RPMI−8226細胞を10ug/ml アイソタイプコントロール抗体(TTCF−S1C1)、CM33322 Ab29、またはCM24002 Ab2の存在下で培養した。48時間後、細胞を洗浄し、MICA表面発現をフローサイトメトリーにより決定した。図49において証明されるとおり、CM24002 Ab2およびCM33322 Ab29は、RPMI−8226細胞から分離するMICAを減少させる
CM33322 mAb 29、CM33322 11およびCM33322 mAb4に対するエピトープ配列を決定するために、実験を行った。簡潔には、エピトープマッピングを、MICA*009細胞外ドメインの全長にわたる一連の重複ペプチドを含むペプチドアレイによって行った。アレイにおけるそれぞれのペプチドは、以前の配列と10アミノ酸によって重複してそれぞれ後の配列を有する、MICA*009参照配列(配列番号:167)からの20アミノ酸直線状配列の長さであった(10aaオフセット(offset)で20aaペプチド)。これらのペプチドは、フレキシブルな(flexible)リンカーの使用を介してスライドガラスに結合させた。Cy5コンジュゲートされた抗ヒトIgG抗体で検出されるペプチドフラグメントに結合される抗体と共に、抗体をスライドとインキュベートした。アレイスポットへの結合は、GenePixマイクロアレイスキャナーで評価した。結果は、mAbs CM33322 Ab4およびCM33322 Ab29がヒトMICAまたはMICBのアルファ−3領域に結合したことを示した。
本発明は、発明を実施するための形態と組み合わせて記載したが、前述の記載は、例示目的のものであり、本発明の範囲を制限するものではないことは理解されるであろう。本発明の範囲は、添付の特許請求の範囲により定義される。以降の特許請求の範囲内に含まれるその他の態様、利点、および改変も存在する。
Claims (56)
- MHCクラスI型ポリペプチド関連性配列A(MICA)に免疫特異的に結合するペプチドを含む組成物であって、前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVHの相補性決定領域(CDR)3と、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVLのCDR3と、を含む、組成物。
- 前記ペプチドが、表1に示す抗体ID11のVHの相補性決定領域(CDR)3と、表1に示す抗体ID11のVLのCDR3と、を含む、請求項1に記載の組成物。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVHのCDR2、または5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVLのCDR2、またはこれらの両方を含む、請求項1または2に記載の組成物。
- 前記ペプチドが、表1に示す抗体ID11のVHの相補性決定領域CDR2、または表1に示す抗体ID11のVLのCDR2、またはこれらの両方を含む、請求項3に記載の組成物。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVHのCDR1、または5以下の保存的アミノ酸置換を有する、表1に示す抗体ID11のVLのCDR1、またはこれらの両方を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記ペプチドが、表1に示す抗体ID11のVHの相補性決定領域CDR1、または表1に示す抗体ID11のVLのCDR1、またはこれらの両方を含む、請求項5に記載の組成物。
- 前記ペプチドが、配列番号150と同一性を有するVH鎖、および配列番号152と同一性を有するVL鎖を含む、抗体または抗体断片であり、
前記VH鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID11のVHの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号150内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID11のVHのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含み、
並びに前記VL鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID11のVLの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号152内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID11のVLのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含む、請求項1〜6のいずれか一項に記載の組成物。 - 前記ペプチドが、配列番号:150を含むVH鎖と、配列番号:152を含むVL鎖と、を含む抗体または抗体断片である、請求項7に記載の組成物。
- 抗癌治療をさらに含む、請求項1〜8のいずれか一項に記載の組成物。
- 医薬組成物として処方された、請求項1〜9のいずれか一項に記載の組成物。
- 対象において癌を処置する方法であって、請求項1〜10のいずれか一項に記載の組成物を対象に投与することを含む、方法。
- ヒドロキサム酸、ボリノスタット、スベロイルアニリドヒドロキサム酸(SAHA、トリコスタチンA(TSA)、LAQ824、パノビノスタット(LBH589)、ベリノスタット(PXD101)、ITF2357 italfarmaco SpA、環状テトラペプチド、デプシペプチド(ロミデプシン、FK228)、ベンズアミド;entinostat(SNDX−275/MS−275)、MGCD0103、短鎖脂肪酸、バルプロ酸、フェニル酪酸、AN−9、pivanex、CHR−3996、およびCHR−2845からなる群から選択されるヒストンデアセチラーゼインヒビター(HDAC)をさらに含む、請求項1〜8のいずれか一項に記載の組成物。
- ボルテゾミブ、NPI−0052、カーフィルゾミブ(PR−171)、CEP 18770、およびMLN9708からなる群から選択されるプロテアソーム阻害剤をさらに含む、請求項1〜8のいずれか一項に記載の組成物。
- 抗−CTLA−4抗体またはペプチド、抗−PD−1抗体またはペプチド、抗−PDL−1抗体またはペプチド、抗−OX40抗体またはペプチド、抗−GITR抗体またはペプチド、抗−LAG−3抗体またはペプチド、および抗−TIM−3抗体またはペプチドからなる群から選択される1つ以上のさらなる薬剤をさらに含む、請求項1〜8のいずれか一項に記載の組成物。
- 化学療法、放射線療法、サイトカイン、ケモカインおよび他の生体シグナル伝達分子、腫瘍特異的ワクチン、細胞癌ワクチン(例えば、GM−CSF形質導入癌細胞)、腫瘍特異的モノクローナル抗体、自己および同種異系の幹細胞レスキュー(例えば、移植片対腫瘍効果を増強させる)、分子標的療法、抗脈管形成療法、および遺伝子治療からなる群から選択される癌の処置のために使用される1つ以上のさらなる薬剤をさらに含む、請求項1〜8のいずれかに記載の組成物。
- MHCクラスI型ポリペプチド関連性配列A(MICA)またはそれらのエピトープに免疫特異的に結合するペプチドをコードする核酸を含む組成物であって、
前記ペプチドは、配列番号2、77、96、113、131または150と同一性を有するVH鎖、および配列番号11、79、98、115、133、152または170と同一性を有するVL鎖を含む、抗体または抗体断片であり、
前記VH鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1、6、7、8、9または11のVHの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号2、77、96、113、131または150内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1、6、7、8、9または11のVHのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含み、
並びに前記VL鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1、6、7、8、9または11のVLの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号11、79、98、115、133または152内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1、6、7、8、9または11のVLのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含む、組成物。 - MHCクラスI型ポリペプチド関連性配列A(MICA)またはそれらのエピトープに免疫特異的に結合するペプチドをコードする核酸を含む組成物であって、前記核酸は、配列番号:149に対し少なくとも約75%、80%、90%、95%、99%またはそれ以上の、または完全(100%)配列同一性を有するヌクレオチド配列を含む、組成物。
- MHCクラスI型ポリペプチド関連性配列A(MICA)またはそれらのエピトープに免疫特異的に結合するペプチドをコードする核酸を含む組成物であって、前記核酸は、配列番号:151に対し少なくとも約75%、80%、90%、95%、99%またはそれ以上の、または完全(100%)配列同一性を有するヌクレオチド配列を含む、組成物。
- 配列番号:149に対し少なくとも約75%、80%、90%、95%、99%またはそれ以上の、または完全(100%)配列同一性を有するヌクレオチド配列を含む、単離された核酸。
- 配列番号:151に対し少なくとも約75%、80%、90%、95%、99%またはそれ以上の、または完全(100%)配列同一性を有するヌクレオチド配列を含む、単離された核酸。
- 配列番号:150に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を有するペプチドをコードするヌクレオチド配列を含む、単離された核酸。
- 配列番号:152に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を有するペプチドをコードするヌクレオチド配列を含む、単離された核酸。
- MHCクラスI型ポリペプチド関連性配列A(MICA)に免疫特異的に結合するペプチドを含むキメラ抗原受容体(CAR)であって、前記ペプチドは、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9または11のVHの相補性決定領域CDR3、および5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9または11のVLのCDR3を含む、キメラ抗原受容体(CAR)。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9または11のVHのCDR3、および表1に示す抗体ID1、6、7、8、9または11のVLのCDR3を含む、請求項23に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9または11のVHのCDR2、または5以下の保存的アミノ酸置換を有する、抗体ID1、6、7、8、9または11のVLのCDR2、またはこれらの両方を含む、請求項23〜24のいずれか一項に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR2、または表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR2、またはこれらの両方を含む、請求項25に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR1、または5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR1、またはこれらの両方を含む、請求項23〜26のいずれか一項に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR1、または表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR1、またはこれらの両方を含む、請求項27に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドが、配列番号2、77、96、113、131または150と同一性を有するVH鎖、および配列番号11、79、98、115、133または152と同一性を有するVL鎖を含む、抗体または抗体断片であり、
前記VH鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1、6、7、8、または9のVHの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号2、149、168、186、または204内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1、6、7、8、または9のVHのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含み、
並びに前記VL鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1のVLの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号11、151、170、189、または206内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1のVLのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含む、請求項23〜27のいずれか一項に記載のキメラ抗原受容体(CAR)。 - 前記ペプチドが、配列番号2、77、96、113、131または150を含むVH鎖と、配列番号11、79、98、115、133または152を含むVL鎖と、を含む抗体または抗体断片である、請求項29に記載のキメラ抗原受容体(CAR)。
- 細胞外ヒンジドメイン、T細胞受容体膜貫通ドメイン、および細胞内T細胞受容体シグナル伝達ドメインをさらに含む、請求項23に記載のキメラ抗原受容体(CAR)。
- 前記ペプチドがCD137(4−IBB)シグナル伝達ドメインおよびCD3−ζ鎖を含む、請求項23に記載のキメラ抗原受容体(CAR)。
- 請求項21〜30のいずれかに記載のキメラ抗原受容体(CAR)をコードする核酸分子。
- 請求項33に記載の核酸分子を有するヒトT細胞。
- 請求項34に記載のT細胞を対象に投与することを含む対象において癌を処置する方法であって、前記T細胞はキメラ抗原受容体(CAR)を発現するように修飾された自己T細胞である、方法。
- 5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9または11のVHの相補性決定領域CDR3と、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9または11のVLのCDR3と、を含む、ペプチドをコードするベクター。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9または11のVHのCDR3と、表1に示す抗体ID1、6、7、8、9または11のVLのCDR3と、を含む、請求項36に記載のベクター。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR2、または5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR2、またはこれらの両方を含む、請求項36または37に記載のベクター。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR2、または表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR2、またはこれらの両方を含む、請求項38に記載のベクター。
- 前記ペプチドが、5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR1、または5以下の保存的アミノ酸置換を有する、表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR1、またはこれらの両方を含む、請求項36〜39のいずれか一項に記載のベクター。
- 前記ペプチドが、表1に示す抗体ID1、6、7、8、9若しくは11のVHのCDR1、または表1に示す抗体ID1、6、7、8、9若しくは11のVLのCDR1、またはこれらの両方を含む、請求項40に記載のベクター。
- 前記ペプチドが、配列番号2、77、96、113、131または150と同一性を有するVH鎖、および配列番号11、79、98、115、133または152と同一性を有するVL鎖を含む、抗体または抗体断片であり、
前記VH鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1、6、7、8または9のVHの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号2、149、168、186または204内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1、6、7、8または9のVHのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含み、
並びに前記VL鎖の、CDR1、CDR2、およびCDR3に相当する領域は、表1に示す抗体ID1のVLの、保存的アミノ酸置換を5つ以下で有するCDR1、CDR2、およびCDR3を含み、かつ配列番号11、151、170、189または206内のFR1、FR2、FR3、FR4に相当する領域は、表1に示す抗体ID1のVLのFR1、FR2、FR3、FR4に対し少なくとも80%、85%、90%、95%、96%、97%、98%、99%、または100%同一性を有するアミノ酸配列を含む、請求項36〜41のいずれか一項に記載のベクター。 - 前記ペプチドが、配列番号2、77、96、113、131または150を含むVH鎖と、配列番号11、79、98、115、133または152を含むVL鎖と、を含む抗体または抗体断片である、請求項42に記載のベクター。
- 前記ベクターがアデノウイルスベクターである、請求項36〜43のいずれか一項に記載のベクター。
- MHCクラスI型ポリペプチド関連性配列A(MICA)に免疫特異的に結合する抗体またはそれらのフラグメントであって、前記抗体またはそれらのフラグメントは、
配列番号:150の配列のVHに示されるVH CDR1、VH CDR2、およびVH CDR3を含む重鎖可変領域(VH);および
配列番号:152の配列のVLに示されるVL CDR1、VL CDR2、およびVL CDR3を含む軽鎖可変領域(VL)
を含む、抗体またはそれらのフラグメント。 - 前記VH領域が
配列番号:154を含むVH CDR1;
配列番号:156を含むVH CDR2;および
配列番号:158を含むVH CDR3;
またはVH CDR1、CDR2、および/またはCDR3において5以下の保存的アミノ酸置換を有するそれらの変異体を含む、請求項45に記載の抗体またはフラグメント。 - 前記VL領域が
配列番号:161を含むVL CDR1、
配列番号:163を含むVL CDR2、および
配列番号:165を含むVL CDR3、
またはVL CDR1、CDR2、および/またはCDR3において5以下の保存的アミノ酸置換を有するそれらの変異体を含む、請求項46に記載の抗体またはフラグメント。 - 前記VH領域が、CDR内ではない残基において5以下の保存的アミノ酸置換を有する配列番号:150に示すアミノ酸配列またはその変異体を含み、および前記VL領域が、CDR内ではない残基において5以下の保存的アミノ酸置換を有する配列番号:152に示すアミノ酸配列またはその変異体を含む、請求項47に記載の抗体またはフラグメント。
- 前記抗体が、配列番号:150の配列のVHに示されるVH;および配列番号:152の配列のVLに示される軽鎖可変領域(VL)を含む、請求項48に記載の抗体またはフラグメント。
- 前記抗体がヒト、ヒト化またはキメラである、請求項45〜49のいずれかに記載の抗体またはフラグメント。
- MHCクラスI型ポリペプチド関連性配列A(MICA)に免疫特異的に結合する抗体またはそれらのフラグメントであって、前記抗体は、
配列番号:154に示すアミノ酸配列を含む重鎖可変領域(VH)CDR1、
配列番号:156に示すアミノ酸配列を含むVH CDR2、および
配列番号:158に示すアミノ酸配列を含むVH CDR3、または5以下の保存的アミノ酸置換を有するそれらの変異体
を含む、抗体またはそれらのフラグメント。 - 前記抗体が、
配列番号:161に示すアミノ酸配列を含む軽鎖可変領域(VL)CDR1、
配列番号:163に示すアミノ酸配列を含むVL CDR2、および
配列番号:165に示すアミノ酸配列を含むVL CDR3、またはVL CDR1、CDR2および/またはCDR3において5以下の保存的アミノ酸置換を有するそれらの変異体
を含む、請求項51に記載の抗体またはそれらのフラグメント。 - 重鎖可変領域(VH)および軽鎖可変領域(VL)を含む単離された抗体またはそれらのフラグメントであって、前記VH領域は配列番号:150のアミノ酸配列を含み、VL領域は配列番号:152のアミノ酸配列を含む、単離された抗体またはそれらのフラグメント。
- 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36〜43のいずれか一項に記載のベクター。
- ウイルスベクターが、ポックスウイルス、アデノウイルス、レトロウイルス、ヘルペスウイルス、およびアデノ随伴ウイルスからなる群から選択される、請求項54に記載のベクター。
- ベクターが発現ベクターである、請求項36〜43のいずれか一項に記載のベクター。
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EA201591559A1 (ru) | 2016-03-31 |
WO2014144791A3 (en) | 2014-11-27 |
US10745483B2 (en) | 2020-08-18 |
EP3666886A1 (en) | 2020-06-17 |
MX2015011075A (es) | 2015-10-29 |
JP6397886B2 (ja) | 2018-09-26 |
CA2907249A1 (en) | 2014-09-18 |
CN105142668A (zh) | 2015-12-09 |
NZ629816A (en) | 2017-07-28 |
US20160046716A1 (en) | 2016-02-18 |
KR20150130462A (ko) | 2015-11-23 |
ES2779398T3 (es) | 2020-08-17 |
EP2970908B1 (en) | 2019-12-25 |
AU2014228502A1 (en) | 2015-08-20 |
BR112015021576A2 (pt) | 2017-10-10 |
SG11201506766PA (en) | 2015-09-29 |
HK1219983A1 (zh) | 2017-04-21 |
WO2014144791A2 (en) | 2014-09-18 |
CN105142668B (zh) | 2018-04-27 |
EP2970908A2 (en) | 2016-01-20 |
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