JP2019077691A - TL1A−Ig融合タンパク質を用いる制御性T細胞の制御のための組成物及び方法 - Google Patents
TL1A−Ig融合タンパク質を用いる制御性T細胞の制御のための組成物及び方法 Download PDFInfo
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Abstract
Description
本願に記載の研究は、米国国立衛生研究所からの助成金(NIH 5P01CA109094)によって一部指示された。従って、政府は本発明にある権利を有する。
本願は、2013年1月9日に出願された米国仮出願第61/750,672号;2013年1月17に出願された米国仮出願第61/753,634号;2013年7月2日に出願された米国仮出願第61/842,127号;及び2013年7月8日に出願された米国仮出願第61/843,558号の優先権の利益を主張し、その各々の全体の内容が参照によって本明細書に組み込まれる。
本明細書で使用される用語「単離された」は、参照される物質が通常見出される環境から除かれることを意味する。従って、単離された生物学的物質は細胞成分、すなわち該物質が見出されまたは産生される細胞の成分を含まないことがある。単離された核酸分子は、例えば、PCR産物、単離されたmRNA、cDNAまたはその制限フラグメントを含むが、これらに限定されない。単離された核酸はまた、例えば、ベクター、プラスミド、コスミド、人工染色体等に挿入された配列を含む。単離された核酸は、好ましくは、見出され得るゲノムから切り取られ、好ましくは非制御配列、非コーディング配列、またはゲノム内に見出される時に核酸分子の上流もしくは下流に位置する他の遺伝子に連結されない。単離された核酸は、その天然環境における(すなわち、細胞の核における)核酸の3’及び5’末端とは異なる3’及び5’末端を有する。単離されたタンパク質は、他のタンパク質もしくは核酸またはその両方と会合し得る(該単離されたタンパク質は細胞中でそれらと会合する)か、あるいはそれが膜関連タンパク質である場合には細胞膜と会合し得る。単離された融合タンパク質は、インビトロで該融合タンパク質を産生するために使用される細胞の細胞成分と会合し得る。
本開示は、TNFRSF25(DR3としても知られている)のアゴニストの単独でまたは併用療法の一部としてのいずれかでの投与を含む方法を提供する。本開示は、新規なTNFRSF25アゴニスト、例えば本明細書に記載のTL1A融合タンパク質を提供する。しかしながら、本明細書ではまた、当該分野で知られている他のTNFRSF25アゴニストの使用を含む新規な方法を提供する。例えば、本明細書に開示された併用療法(mTOR阻害剤、例えばラパマイシン及び/またはIL−2とTNFRSF25アゴニストとの同時投与を含む)で使用され得るTNFRSF25アゴニストの非限定的な例は、例えば、小分子、抗体及び融合タンパク質を含む。かかるTNFRSF25アゴニストの非限定的な例は、例えば米国付与前公表番号第2011/0243951号、同第2012/0029472号及び同第2012/0135011号(全てPodackら)に記載されている。抗TNFRSF25抗体を調製する方法は、PodackらによるUS2012/0029472に記載されている。本方法、例えば、本明細書に開示された併用療法は、当該分野で知られている任意の好適なTNFRSF25の使用を画する。実施形態によっては、TNFRSF25アゴニストは、Treg細胞の拡張を亢進するものである。
aaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgacacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggacccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctccttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号5);及び
kgqefapshqqvyaplradgdkprahltvvtqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgpmfslqegdklmvnvsdislvdytkedktffgafll(配列番号6)。
ataaaaacatgtggtggtggcagcaaacctcccacgtgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtagacgtgagccaggaagaccccgatgtcaagttcaactggtacgtaaacggcgcggaggtgcatcatgcccagacgaagccacgggagacgcagtacaacagcacatatcgtgtggtcagcgtcctcaccgtcacgcaccaggactggctgaacggcaaggagtacacgtgcaaggtctccaacaaagccctcccggtccccatccagaaaaccatctccaaagacaaagggcagccccgagagcctcaggtgtacaccctgcccccgtcccgggaggagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgtcgtggagtgggagaacagcgggcagccggagaacacctacaagaccaccccgcccgtgctggactccgacggctcctacttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcag(配列番号7)
iktcgggskpptcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpdvkfnwyvngaevhhaqtkpretqynstyrvvsvltvthqdwlngkeytckvsnkalpvpiqktiskdkgqprepqvytlppsreeltknqvsltclvkgfypsdivvewensgqpentykttppvldsdgsyflyskltvdksrwqqgnvfscsvmhealhnhytq(配列番号8)
atggagacagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgacctcgagataaaaacatgtggtggtggcagcaaacctcccacgtgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtagacgtgagccaggaagaccccgatgtcaagttcaactggtacgtaaacggcgcggaggtgcatcatgcccagacgaagccacgggagacgcagtacaacagcacatatcgtgtggtcagcgtcctcaccgtcacgcaccaggactggctgaacggcaaggagtacacgtgcaaggtctccaacaaagccctcccggtccccatccagaaaaccatctccaaagacaaagggcagccccgagagcctcaggtgtacaccctgcccccgtcccgggaggagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgtcgtggagtgggagaacagcgggcagccggagaacacctacaagaccaccccgcccgtgctggactccgacggctcctacttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcaggaattcaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgacacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggacccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctccttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号9);及び
metdtlllwvlllwvpgstgdleiktcgggskpptcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpdvkfnwyvngaevhhaqtkpretqynstyrvvsvltvthqdwlngkeytckvsnkalpvpiqktiskdkgqprepqvytlppsreeltknqvsltclvkgfypsdivvewensgqpentykttppvldsdgsyflyskltvdksrwqqgnvfscsvmhealhnhytqefkgqefapshqqvyaplradgdkprahltvvtqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgpmfslqegdklmvnvsdislvdytkedktffgafll(配列番号10)。
cgggcccagggagaggcctgtgtgcagttccaggctctaaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgagacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggagccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctctttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号11)(ヒトTL1Aの細胞外ドメインをコードする);及び
raqgeacvqfqalkgqefapshqqvyaplradgdkprahltvvrqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgamfslqegdklmvnvsdislvdytkedktffgafll(配列番号12)(ヒトTL1Aの細胞外ドメイン)。
tgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa(配列番号13);及び
cdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk(配列番号14)(ヒトIgGのヒンジ、CH2及びCH3領域)。
tgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaagaattccgggcccagggagaggcctgtgtgcagttccaggctctaaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgagacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggagccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctctttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号15);及び
cdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkefraqgeacvqfqalkgqefapshqqvyaplradgdkprahltvvrqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgamfslqegdklmvnvsdislvdytkedktffgafll(配列番号16)である。
実施形態によっては、本明細書では、例えば、それを必要とするヒト患者における、抗原特異的免疫応答を調節し、及び/または抗原特異的免疫応答に関連した疾患または障害を治療し、該疾患または障害の1またはそれ以上の症候を治療するための併用療法が提供される。実施形態によっては、本方法は、TNFRSF25アゴニスト(例えば、TL1A融合タンパク質、アゴニスティック抗TNFRSF25抗体、TNFR25アゴニストの小分子アゴニスト等)、及びmTOR阻害剤の有効量を含む組成物を、それを必要とする患者に投与することを含む。実施形態によっては、上記方法は、TNFRSF25アゴニスト及びmTOR阻害剤を含む併用療法を患者に投与することを含む。
インターロイキンを含む本明細書に開示された組成物及び方法のいずれかにおいて、インターロイキンは、例えば、TNFRSF25アゴニストとの併用療法において投与される場合に、Treg細胞の拡張に対する所望の相乗効果を達成する任意のインターロイキンでよい。実施形態によっては、インターロイキンはIL−2である。実施形態によっては、インターロイキンはIL−7である。実施形態によっては、インターロイキンはIL−15である。
実施形態によっては、本明細書では、ヒトTL1A−Ig融合タンパク質を含む組成物であって、該融合タンパク質が、(a)TNFRSF25に特異的に結合するポリペプチドを含む第1ポリペプチド、及び(b)免疫グロブリン(Ig)ポリペプチドを含む第2ポリペプチドを含む、組成物が提供される。実施形態によっては、第1ポリペプチドは、ヒトTL1Aポリペプチドの細胞外ドメインまたはそのフラグメントを含み、該フラグメントはTNFRSF25に特異的に結合できる。実施形態によっては、それを必要とするヒトに投与される時に、本組成物は、ヒトでのナイーブCD4 T細胞の頻度を減少させる。
本明細書に記載の組成物は、当該分野で公知の任意の好適な投与経路によって投与され得る。例えば、TNFRSF25アゴニスト、インターロイキン、及びmTOR阻害剤は、非経口的投与(例えば、静脈内、腹腔内、硬膜外、鞘内、筋肉内、管腔内、気管内、皮内、または皮下)のために一緒にまたは別箇に製剤化され得る。
本明細書では、それを必要とするヒト患者における抗原特異的免疫応答を調節する方法が記載される。実施形態によっては、該方法は、本明細書に記載のTL1A融合タンパク質を含む組成物を該患者に投与することを含み得る。典型的には、TL1A融合タンパク質を含む該組成物は、TL1A融合タンパク質の治療上有効量を含む。具体的な実施形態では、抗原特異的免疫応答は阻害される。
以下は、以下の実施例で使用される材料及び方法である。
Foxp3+RFP+(FIRマウス)及びバックグラウンド系統のFoxp3+GFP+レポーターマウス(ご親切にもRichard Flavell博士及びAlexander Rudensky博士によって提供を受けた[Wan,Y.Y.及びR.A.Flavell.2005年 バイシストロニックなレポーターでのFoxp3発現サプレッサT細胞同定 Proc.Natl.Acad.Sci.USA 102:5126?5131参照])、CD4−/−マウス、NOD.SCID/γc−/−(NSG)、OT−II及びOT−II/FIRマウスを、動物施設で飼育した。マウスは6〜12週齢で使用し、病原無しの条件下で維持した。先に記載のようにしてTreg養子移入モデルを樹立した(Schreiberら Oncoimmunology.2012年8月1日;1(5):642−648参照)。
RNeasyキット(Qiagen)を用いてアカゲザル末梢血単核細胞の調製物から総RNAを単離した。次いで、5’RACE(Invitrogen)を用いて、5’キャップかつ3’ポリA鎖RNAのPCR増幅によってアカゲザルcDNAライブラリを作製した。アカゲザルTL1Aの細胞外ドメイン(アミノ酸73〜2529)を、以下のプライマー:フォワード5’−AAAGGACAGGAGTTTGCACC−3’(配列番号17)、リバース5’−CTATAGTAAGAAGGCTCCAAA−3’(配列番号18)を用いて増幅し、アカゲザルIgG1のヒンジ−CH2−CH3ドメインに融合し、以下のプライマー:フォワード5’−ATAAAAACATGTGGTGGTGG−3’(配列番号19)及びリバース5’−CTGCGTGTAGTGGTTGTGCA−3’(配列番号20)を用いて増幅し、哺乳動物発現ベクターpVITRO2−hygro−mcs(Invivogen)の第2の複数クローニング部位にクローン化した。
核酸配列:
aaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgacacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggacccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctccttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号5);及び
アミノ酸配列:
kgqefapshqqvyaplradgdkprahltvvtqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgpmfslqegdklmvnvsdislvdytkedktffgafll (配列番号6)。
核酸配列:
ataaaaacatgtggtggtggcagcaaacctcccacgtgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtagacgtgagccaggaagaccccgatgtcaagttcaactggtacgtaaacggcgcggaggtgcatcatgcccagacgaagccacgggagacgcagtacaacagcacatatcgtgtggtcagcgtcctcaccgtcacgcaccaggactggctgaacggcaaggagtacacgtgcaaggtctccaacaaagccctcccggtccccatccagaaaaccatctccaaagacaaagggcagccccgagagcctcaggtgtacaccctgcccccgtcccgggaggagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgtcgtggagtgggagaacagcgggcagccggagaacacctacaagaccaccccgcccgtgctggactccgacggctcctacttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcag(配列番号7);及び
アミノ酸配列:
iktcgggskpptcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpdvkfnwyvngaevhhaqtkpretqynstyrvvsvltvthqdwlngkeytckvsnkalpvpiqktiskdkgqprepqvytlppsreeltknqvsltclvkgfypsdivvewensgqpentykttppvldsdgsyflyskltvdksrwqqgnvfscsvmhealhnhytq(配列番号8)。
DNA配列:
atggagacagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgacctcgagataaaaacatgtggtggtggcagcaaacctcccacgtgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtagacgtgagccaggaagaccccgatgtcaagttcaactggtacgtaaacggcgcggaggtgcatcatgcccagacgaagccacgggagacgcagtacaacagcacatatcgtgtggtcagcgtcctcaccgtcacgcaccaggactggctgaacggcaaggagtacacgtgcaaggtctccaacaaagccctcccggtccccatccagaaaaccatctccaaagacaaagggcagccccgagagcctcaggtgtacaccctgcccccgtcccgggaggagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgtcgtggagtgggagaacagcgggcagccggagaacacctacaagaccaccccgcccgtgctggactccgacggctcctacttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcaggaattcaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgacacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggacccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctccttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag(配列番号9);及び
アミノ酸配列:
metdtlllwvlllwvpgstgdleiktcgggskpptcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpdvkfnwyvngaevhhaqtkpretqynstyrvvsvltvthqdwlngkeytckvsnkalpvpiqktiskdkgqprepqvytlppsreeltknqvsltclvkgfypsdivvewensgqpentykttppvldsdgsyflyskltvdksrwqqgnvfscsvmhealhnhytqefkgqefapshqqvyaplradgdkprahltvvtqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgpmfslqegdklmvnvsdislvdytkedktffgafll(配列番号10)。
核酸配列:
cgggcccagggagaggcctgtgtgcagttccaggctctaaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgagacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggagccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctctttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag (配列番号:11);及び
アミノ酸配列:
raqgeacvqfqalkgqefapshqqvyaplradgdkprahltvvrqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgamfslqegdklmvnvsdislvdytkedktffgafll(配列番号:12)。
核酸配列:
tgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa(配列番号:13);及び
アミノ酸配列:
cdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk(配列番号:14)。
核酸配列:
tgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaagaattccgggcccagggagaggcctgtgtgcagttccaggctctaaaaggacaggagtttgcaccttcacatcagcaagtttatgcacctcttagagcagacggagataagccaagggcacacctgacagttgtgagacaaactcccacacagcactttaaaaatcagttcccagctctgcactgggaacatgaactaggcctggccttcaccaagaaccgaatgaactataccaacaaattcctgctgatcccagagtcgggagactacttcatttactcccaggtcacattccgtgggatgacctctgagtgcagtgaaatcagacaagcaggccgaccaaacaagccagactccatcactgtggtcatcaccaaggtaacagacagctaccctgagccaacccagctcctcatggggaccaagtctgtgtgcgaagtaggtagcaactggttccagcccatctacctcggagccatgttctccttgcaagaaggggacaagctaatggtgaacgtcagtgacatctctttggtggattacacaaaagaagataaaaccttctttggagccttcttactatag (配列番号:15);及び
アミノ酸配列:
cdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkefraqgeacvqfqalkgqefapshqqvyaplradgdkprahltvvrqtptqhfknqfpalhwehelglaftknrmnytnkfllipesgdyfiysqvtfrgmtsecseirqagrpnkpdsitvvitkvtdsypeptqllmgtksvcevgsnwfqpiylgamfslqegdklmvnvsdislvdytkedktffgafll(配列番号:16)。
標準的エレクトロポレーション及び脂質系トランスフェクション法を用いて、NIH−CHO細胞のトランスフェクションを行った。好適な抗生物質(ハイグロマイシン)でトランスフェクトされた細胞を選択し、より高い力価産生クローンを同定するために限界希釈シングルセルクローニング法を限定することによって更に選択した。次いで、選択されたクローンから血清を除き、血清無しの条件下で成長するように適合した。次いで、血清無しの培地で成長する安定クローンを、融合タンパク質製造のために、ホロファイバーカートリッジシステムにロードした。NIH−CHO−hTL1A−Ig細胞をOPTI−CHO培地で維持し、hTL1A−Ig含有細胞培養上清を回収した。hTL1A−Igの精製は、標準的方法を用いてプロテインAまたはプロテインGカラムに結合することによって行い、基本的な溶出バッファを用いてカラムから溶出して、融合タンパク質の好適な機能を維持した。基本的なバッファでの溶出は、酸性バッファでの溶出が機能活性を破壊したので必須であった。溶出後、タンパク質画分をプールし、標準的なタンパク質アッセイ(Bradford)及びIgG鎖の検出用の特定のELISAアッセイの両方を用いて定量した。次いで、精製したタンパク質をPBSに透析し、−80℃で保存した。
フローサイトメトリー、ELISA及びインビボ試験で使用するための商業的な抗体は、BD Pharmingen、eBioscienceまたはBioLegendから購入した。アメリカンハムスターIgGアイソタイプコントロールは、eBioscienceから得た。マウスTNFRSF25(4C12、アゴニスティック)に対する抗体を産生するアメリカンハムスターハイブリドーマは、Fangら 2008年に記載のように作製した。アレルギー肺炎症の発症のおけるTNF受容体スーパーファミリー(TNFRSF25)の必須の役割。J Exp Med 205:1037−1048。簡単には、4C12、hTL1A−I及びrmTL1A−Igは、ホローファイバー・バイオリアクター(Fibercell Systems,Frederick,MD)で産生し、プロテインG(4C12)またはプロテインA((TL1A−Ig)カラム(GE Healthcare,UK)上で血清無しの上清から精製した。フローサイトメトリー分析用に、脾臓及びリンパ節から単細胞浮遊液を調製した。106細胞を抗マウスCD16/CD32で予めブロックし、異なった抗体組み合わせで染色した。細胞内染色は、標準的手法に従って行った。フローサイトメトリーによる分析は、Becton Dickinson Fortessa装置で行い、FACSDIVAまたはFlowJoソフトウエアを分析に用いた。
10〜40ng/ウェルを有する4〜12% SDS−PAGEゲルのローディング、標準的バッファ及び電圧を用いるゲル操作、標準的方法を用いるPVDF膜への移行、及びa−hIgG−HRPを用いるワンステップ染色及びPicoまたはFemtoアルカリホスファターゼ系型検出試薬(Pierce)を用いる次の検出を含む標準的方法を用いた。
ヒトTNFRSF25(hTNFRSF25)をクローン化し、p815細胞(ATCCから購入)をトランスフェクトするために使用した。細胞を標準的なエレクトロポレーションまたは脂質系トランスフェクション法を用いてトランスフェクトした。次いで、トランスフェクトしたp815細胞は、精製したhTL1A−Ig(1pg/ml−1μg/ml)の濃度を増加させながら同時インキュベートし、製造者のプロトコール(Roche,カスパーゼ3活性アッセイ,製品番号12012952001)に従ってカスパーゼ検出アッセイを行った。
これらのアッセイは、Khanら,Immunol.2013年2月15日;190(4):1540−50に記載のようにして行った。
選択的中絶(妊娠期間の12〜20週齢,Advanced Bioscience Resources)からのヒト胎児肝臓を調査基準価格で入手した。CD34+細胞は、単細胞浮遊液(CD34+セレクションキット;Miltenyi Biotec,Auburn,CA)の密度勾配遠心に従う製造者の教示に従って免疫磁性ビーズを用いて濃縮した。単離したCD34+細胞の純度をフローサイトメトリーで評価し、85%超であった。後のHLAタイピングのために細胞をアリコートし、凍結し、亜致死照射新生児NSGマウスに移植した。10%ヒト血清、インターロイキン(IL)−3、IL−6の各10ng/ml及び幹細胞因子(SCF)をIMDM中に含む培養液にHLAタイピングされたCD34+細胞造血幹細胞(HSC)を3〜5日間入れた。移植の日に、培養皿から細胞を採取し、HBSSで洗浄し、増殖及び分化能を評価するためにCFU及びLTC−ICアッセイを行った。標準試薬(StemCell Inc.)及び製造者によって公表された方法を用いてこれらのアッセイを行った。CFU能は、SCF、GM−CSF、IL−3及びEPOで補充したメチルセルロース培地での14日間培養後の骨髄前駆細胞と同一であった。これらのアッセイは、単離したHSCの全体形態的特徴及びコロニー数が予測した限度内にあるか否かを容易に明らかにする。一対一交配から作製された1日令NSGマウスは、24時間照射後、里母親で飼育し(亜致死,1Gy,全身照射)、その時点で、ハミルトンシリンジ及び30ゲージ1/2インチのニードルを用いて、20μlの体積中、1x106〜2x106予備培養HSC肝内(i.h.)で移植した。仔ネズミを直ぐに里母親に戻し、28日間離乳するまで乳を飲ませた。フローサイトメトリーによってネズミ及びヒトCD45+細胞の相対的パーセンテージを決定することによって15週齢の末梢血でヒト/マウスキメラ性を評価した。一旦ヒトCD45+が検出されると、全ての採血でヒトCD3、CD4、CD8、CD11c及びCD19を含むように分析を拡大した。末梢血中のヒトCD45+細胞が60%(NSG−hu)を超える場合に成功的に生着したマウスを選択した。
非ヒト霊長類(NHP)(インド起源アカゲザル)におけるTL1A−Igの安全性及び有効性を決定した。規定どおりのスクリーニング及び60日間隔離の後に、静脈内(IV)ボーラス投与(15分)で0日にアカゲザル(rm)TL1A−Igまたはヒト(h)TL1A−IgをNHPに投与した。動物の体重及びケージ側の観察を毎日行い、全血算定法、規定どおりの化学、CD4 TruCounts、血清分離及びフローサイトメトリー分析のために末梢血を集めた。フローサイトメトリー分析のためには、Countess自動細胞数カウンタで末梢血細胞を計数し、1.5x106細胞のアリコートを試験管、FMO(Fluorescent Minus One)、コントロール及び補正チューブ(compensation tubes)に分配した。生死アクアブルー弁別装置(Life Technologies)で試験管をD−PBS及び0.5% FBSで染色した。試験サンプル及び好適なコントロールを所定の抗体カクテル(BD Becton Dickinson,eBioscienceまたはLife Technologiesから購入)で30分間表面染色した。分子内染色のために、4℃で30分間Fix/perm溶液(eBioscience)で透過した。細胞を洗浄し、30分間、抗FoxP3抗体で細胞内染色した。染色後、細胞を洗浄し、BD(商標)LSRIIフローサイトメトリー(Beckton Dickinso(BD))での取得のために300μL FAC洗浄バッファに再懸濁した。細胞を取得し、FlowJoソフトウエア(Tree Star,Inc.,Ashland,OR)で分析した。CD4/CD8Trucountについては、CD45、CD3、CD4及びCD8抗体をTruCountチューブ(BD,製品番号340334)に分散し;50uLサンプルを加え、暗所で室温で15分間染色した。次いで、450μL FACS溶解液でサンプルを溶解し、15分間インキュベートした。Cサイトメーター(Calibur,BD)で試験管を分析した。事象は、側方散乱(SSC)ドットプロットにおいてリンパ球にゲートをかけ、CD45−陽性集団を選択した後、報告した:CD3+CD4+T細胞及びCD3+CD8+T細胞。血清サイトカインの多重分析のために、所定に日から得られた血清を集め、サンプル及び標準曲線用のコントロールをフィルタプレートに置き、1/4に希釈し、室温で2時間、抗サイトカインビーズでインキュベートした。内容を除去し、ビオチン化検出抗体の混合物を各ウェルに添加前にバッファで2回洗浄した。検出抗体で1時間インキュベートした後、プレートを2回洗浄し、ストレプトアビジン−PEで30分間インキュベートした。再度、プレートを洗浄し、150μLシース液でウェルを再懸濁し;次いで、プレートを読み、Luminex(登録商標)SDアナライザー(Life Technologies,Inc.)で分析した。PEシグナル(中央蛍光強度,MFI)はサンプルに存在する各サイトカインの量に比例し;濃度を標準曲線から計算した。
ABI Prism(登録商標)プログラム(Applied Biosystems)を用いて、グラフ化及び統計的分析の全てを行った。スチューデントT検定を用いてペア分析を行った。2超の症状を有する症状の分析は、ターキー事後検定で片側ANOVAを用いて行った。有意差は図に*(p<0.05);**(p<0.01);及び***(p<0.001)として示す。
本実施例は、TNFRSF25によって刺激されたTreg増殖がコグネート抗原に依拠することを証明する。
本実施例は、ヒトTL1A−Ig融合タンパク質はヒトTregの強力な増殖を全身的に及びヒト化マウスの粘膜で誘導したことを証明する。
本実施例は、TL1A−Igがヒト化マウス及び霊長類で、インビボで、コグネートTreg細胞の増殖を安全かつ選択的に刺激することができたことを証明する。
齧歯動物モデルの固有の制限は、病原無しの条件下で繁殖され飼育された研究室動物の外来抗原チャレンジの高度に制御されかつ制限された歴史に関連する。TNFRSF25アゴニストの抗原依存的活性を考慮すると、この限界は、これらの物質のNHPへの翻訳試験の重要な結果を有するが、外来抗原曝露の歴史は劇的により多様である。この疑問を解決するために、アカゲザルTL1A−Ig(rmTL1A−Ig)を産生しNHPで試験した。処置済みナイーブインド起源アカゲザル(非ヒト霊長類(NHP))を取得し、飼育し、Advanced Bioscience Laboratories(ABL,Rockville,MD)で専門職員によって処置した。アカゲザルTL1A−Ig(rmTL1A−Ig)及びヒト(h)TL1A−Igを製造し、上記のようにして精製し、全体積10ml PBSで希釈したブラインド化チューブ中の所定の濃度でABL職員に移送した。清浄60日検疫後に、ベースラインの全血球数(CBC)及び血清化学を、rmTL1A−Ig及びhTL1A−Igの計画された静脈内投与前の14日に得た。試験の0日に単回IV注射によって、2動物には0.5mg/kg rmTL1A−Igを投与し、4動物には1.5mg/kg rmTL1A−Igを投与し、2動物には1.5mg/kg hTL1A−Igを投与した。TL1A−Ig半減期、Treg拡張、Tconv亜群、及び活性化分析及びサイトカインプロファイルを、試験の21日目に殺処分された動物由来の組織病理学と共に、実験の21日間に渡る連続採血によって監視した。
実施例2〜4のデータは、インビボにてマウス、NSG−huおよびNHPでTL1A−IgがコグネートTreg細胞の増殖を安全にかつ選択的に刺激することができる分子であることを示している。特別な関心事は、TL1Aのトランスジェニック発現がIBDに罹患易くすることを証明するヒト及びマウスでの実験において、TL1A多形をIBDに関連付ける疫学的データがあるために、炎症性腸疾患(IBD)への可能な感受性であった。腸での内因性「外来」抗原への寛容は特にTregの免疫抑制活性に依るので、NHPでのTNFRSF25の調節は同様な免疫病理学をもたらすだろうと推測された。かかる毒性は、これらの試験期間での行動変化、下痢または体重減少によって証明されるようにこれらの試験で観察されず、末梢血でのエフェクター細胞活性化または炎症性サイトカイン産生を広める証拠はなかった。終末器官組織病理学は、組織免疫病理学の明白な兆候を示すことなく、末端回腸及びS状結腸内でのリンパ系細胞の軽度集積のみを証明した。
本実施例は、低用量または極低用量のIL−2とTNFRSF25アゴニストとの併用、例えばTL1A−Ig融合タンパク質またはアゴニスティック抗TNFRSF25抗体4C12がTreg細胞の拡張に対する相乗効果をインビボで有したとの驚くべきかつ予測できない発見を証明する。
本実施例は、ラパマイシンとTL1A−Ig融合タンパク質との併用がインビボでTreg細胞を保存した一方、同時エフェクターT細胞活性化を排除したとの驚くべきかつ予測できない発見を証明する。
hTL1A−Ig融合タンパク質は静脈内投与用に緩衝化生理食塩水で調合する。0.1mg/kg/日〜10mg/kg/日hTL1A−Ig融合タンパク質の範囲内で増加し、上記実施例1に記載のように調製、単離された投薬は、固体臓器または幹細胞移植前に、数日間、誘導剤としてヒト患者に投与される。次いで、数週間の期間に渡って連続採血によってこの治療の有効性を測定する、そこでは、処置した対象の末梢血でTreg細胞、Tエフェクター(Teff)細胞及び炎症性サイトカインの頻度を測定する。タクロリムスまたは他のmTOR阻害剤を含むがこれらに限定されない標準的な免疫抑制維持療法、シクロスポリン阻害剤、及びプレドニゾン及びメチルプレドニゾンを含むステロイドレジメン、の早期離乳の能力に基づいて、処置した対象におけるこの治療の長期間の利益も測定する。
hTL1A−Ig融合タンパク質は、上記実施例1に記載のように調製、単離された上記予言的実施例1に効果的であると見出された投薬量(例えば、0.1mg/kg/日〜10mg/kg/日)での静脈内投与用に緩衝化生理食塩水で調合する。固体臓器または幹細胞移植前に、数日間、誘導剤としてヒト患者に投与される。hTL1A融合タンパク質の投与の1日または2日前、同日、またはその1日または2日後に、患者はまた、低用量IL−2(300,000単位)または極低用量(30,000単位)のいずれか、あるいはIL−2の30,000〜300,000単位/平方メートルの量で静脈内で投与される。
例えば上記実施例1及び3に記載のヒトTL1A−Ig融合タンパク質、またはアゴニスティック抗TNFRSF25抗体は、有効量(例えば、TL1A−Ig融合タンパク質については、上記の予言的実施例1で有効であることが見出された投薬量(例えば、0.1mg/kg/日〜10mg/kg/日の範囲))での静脈投与用に緩衝化生理食塩水で調合され、上記実施例1に記載のように調製、単離される。ヒトTL1A融合タンパク質、またはアゴニスティック抗TNFRSF25抗体は、固体臓器または幹細胞移植の数日前に誘導剤としてヒト患者に投与される。TNFRSF25アゴニストの投与の1日または2日前、同日、またはその1日または2日後に、患者はまた、75〜300マイクログラム/kg体重/日の投薬量でラパマイシンを投与される。
Claims (25)
- それらを必要とする対象における自己免疫疾患の治療に使用するための組み合わせ医薬であって、当該医薬は、
(i)ヒトTL1A−Ig融合タンパク質を含む組成物、及び
(ii)有効量のインターロイキン(IL)−2または有効量のmTOR阻害剤
を組み合わせてなり、
前記組成物は、
(a)腫瘍壊死因子受容体スーパーファミリーであるメンバー25(TNFRSF25)に特異的に結合するヒトTL1Aポリペプチドの細胞外ドメインまたはそのフラグメントを含む第1ポリペプチドと、
(b)免疫グロブリン(Ig)ポリペプチドを含む第2ポリペプチドと、
を含むことを特徴とする組み合わせ医薬。 - 請求項1に記載の組み合わせ医薬において、前記第1ポリペプチドが、(a)配列番号12のアミノ酸配列、または(b)配列番号12と少なくとも90%の配列同一性を有するアミノ酸配列を含むことを特徴とする組み合わせ医薬。
- 請求項1または2に記載の組み合わせ医薬において、前記ヒトTL1A−Ig融合タンパク質がホモ多量体であり、当該ホモ多量体が三量体の二量体であることを特徴とする組み合わせ医薬。
- 請求項1または2に記載の組み合わせ医薬において、前記Igポリペプチドが、IgGポリペプチドのヒンジ領域、CH2ドメイン、及びCH3ドメインの1または複数を含むことを特徴とする組み合わせ医薬。
- 請求項1乃至4の何れか1項に記載の組み合わせ医薬において、前記Igポリペプチドが、(a)配列番号14のアミノ酸配列、または(b)配列番号14と少なくとも90%の配列同一性を有するアミノ酸配列を含むことを特徴とする組み合わせ医薬。
- 請求項1乃至5の何れか1項に記載の組み合わせ医薬において、前記ヒトTL1A−Ig融合タンパク質が、(a)配列番号16のアミノ酸配列、または(b)配列番号16と約95%の配列同一性を有するアミノ酸配列を含むことを特徴とする組み合わせ医薬。
- 請求項1乃至6の何れか1項に記載の組み合わせ医薬において、当該組み合わせ医薬が、Igポリペプチドと結合していない場合に、前記第1ポリペプチドと比べて高いインビボ効果によって特徴付けられることを特徴とする組み合わせ医薬。
- 請求項1乃至7の何れか1項に記載の組み合わせ医薬において、前記IL−2の有効量が、対象に投与される場合に、TL1A−Ig融合タンパク質との併用で、Treg細胞の拡張に対する相乗効果を達成するのに十分な量であることを特徴とする組み合わせ医薬。
- 請求項1乃至8の何れか1項に記載の組み合わせ医薬において、前記IL−2の有効量が、対象に単独で投与される場合に、Treg細胞の至適拡張を誘導するか、またはTreg細胞の拡張を誘導できないであろうIL−2の用量であることを特徴とする組み合わせ医薬。
- 請求項9に記載の組み合わせ医薬において、前記IL−2の用量が、1,000,000単位/平方メートル/日未満であることを特徴とする組み合わせ医薬。
- 請求項10に記載の組み合わせ医薬において、前記IL−2の用量が、30,000〜500,000単位/平方メートル/日の範囲内であることを特徴とする組み合わせ医薬。
- 請求項10に記載の組み合わせ医薬において、前記IL−2の用量が、30,000〜500,000単位/平方メートル/日の範囲内であることを特徴とする組み合わせ医薬。
- 請求項10に記載の組み合わせ医薬において、前記IL−2の用量が、約300,000単位/平方メートル/日であることを特徴とする組み合わせ医薬。
- 請求項1に記載の組み合わせ医薬において、前記mTOR阻害剤がラパマイシンであることを特徴とする組み合わせ医薬。
- それらを必要とする対象における総CD4+細胞のうちCD4+FoxP3+制御性T細胞の頻度の増加に使用するための組み合わせ医薬であって、当該医薬は、
(i)ヒトTL1A−Ig融合タンパク質を含む組成物、及び
(ii)有効量のインターロイキン(IL)−2、
を組み合わせてなり、
前記組成物は、
(a)腫瘍壊死因子受容体スーパーファミリーであるメンバー25(TNFRSF25)に特異的に結合するヒトTL1Aポリペプチドの細胞外ドメインまたはそのフラグメントを含む第1ポリペプチドと、
(b)免疫グロブリン(Ig)ポリペプチドを含む第2ポリペプチドと、
を含むことを特徴とする組み合わせ医薬。 - 請求項15に記載の組み合わせ医薬において、前記ヒトTL1A−Ig融合タンパク質が、(a)配列番号16のアミノ酸配列、または(b)配列番号16と約95%の配列同一性を有するアミノ酸配列を含むことを特徴とする組み合わせ医薬。
- 請求項15または16に記載の組み合わせ医薬において、前記IL−2が、対象に単独で投与される場合に、Treg細胞の至適拡張を誘導するか、またはTreg細胞の拡張を誘導できないであろう用量で投与されることを特徴とする組み合わせ医薬。
- 請求項15乃至17の何れか1項に記載の組み合わせ医薬において、前記IL−2の有効量が、1,000,000単位/平方メートル/日未満であることを特徴とする組み合わせ医薬。
- 請求項18に記載の組み合わせ医薬において、前記IL−2の用量が、30,000〜300,000単位/平方メートル/日の範囲であることを特徴とする組み合わせ医薬。
- 請求項18に記載の組み合わせ医薬において、前記IL−2の用量が、30,000〜500,000単位/平方メートル/日の範囲内であることを特徴とする組み合わせ医薬。
- 請求項18に記載の組み合わせ医薬において、前記IL−2の用量が、約300,000単位/平方メートル/日であることを特徴とする組み合わせ医薬。
- それを必要とする対象におけるエフェクターT細胞の頻度及び/または拡張の減少に使用するための組み合わせ医薬であって、当該医薬は、
(i)ヒトTL1A−Ig融合タンパク質を含む組成物、及び
(ii)有効量のmTOR阻害剤
を組み合わせてなり、
前記組成物は、
(a)腫瘍壊死因子受容体スーパーファミリーであるメンバー25(TNFRSF25)に特異的に結合するヒトTL1Aポリペプチドの細胞外ドメインまたはそのフラグメントを含む第1ポリペプチドと、
(b)免疫グロブリン(Ig)ポリペプチドを含む第2ポリペプチドと、
を含むことを特徴とする組み合わせ医薬。 - 請求項22に記載の組み合わせ医薬において、前記mTOR阻害剤がラパマイシンであることを特徴とする組み合わせ医薬。
- 請求項22に記載の組み合わせ医薬において、前記Igポリペプチドが、IgGポリペプチドのヒンジ領域、CH2ドメイン、及びCH3ドメインを含むことを特徴とする組み合わせ医薬。
- 請求項22乃至24の何れか1項に記載の組み合わせ医薬において、前記ヒトTL1A−Ig融合タンパク質が、(a)配列番号16のアミノ酸配列、または(b)配列番号16と約95%の配列同一性を有するアミノ酸配列を含むことを特徴とする組み合わせ医薬。
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CA2897826C (en) | 2022-09-27 |
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USRE48599E1 (en) | 2021-06-22 |
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