JP2019506897A - ヒトのセレブロンを発現するトランスジェニックマウス - Google Patents
ヒトのセレブロンを発現するトランスジェニックマウス Download PDFInfo
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Abstract
【選択図】図1
Description
本出願は、2016年1月19日に出願された米国仮特許出願第62/280,633号に対する優先権を主張し、その全体が参照により本明細書に組み込まれる。
1.分野
本明細書において、そのゲノムがヒトセレブロン(CRBN)またはその断片をコードする核酸配列を含むトランスジェニックマウスが提供される。このようなトランスジェニックマウスを作製するための方法も本明細書で提供される。さらに、これらのトランスジェニックマウスを、例えば、様々な疾患(がんなど)の治療における特定の化合物の有効性、特異性、毒性、薬物動態、薬力学、作用機序の評価;これらの化合物の投与レジメンの最適化;ならびに、そのような疾患のための他の治療薬との併用療法を研究することに用いる方法が提供される。
がんは、所与の正常組織に由来する異常細胞の数の増大、これらの異常細胞による隣接組織の浸潤、またはリンパ管もしくは血液媒介性の悪性細胞の局所リンパ節及び遠隔部位への伝播(転移)によって主に特徴付けられる。がん患者の治療に使用され得る新しい方法、治療法、及び組成物には大きな需要がある。
1つの態様では、そのゲノムが、ヒトCRBNまたはその断片をコードする核酸配列を含み、内因性マウスCRBNがトランスジェニックマウスにおいて発現されないトランスジェニックマウスが本明細書において提供される。一実施形態では、トランスジェニックマウスのゲノムは、ヒトCRBNをコードする核酸配列を含む。特定の実施形態では、ヒトCRBNをコードする核酸配列は、安定に染色体に組み込まれる。別の実施形態では、トランスジェニックマウスのゲノムは、ヒトCRBNの断片をコードする核酸配列を含む。特定の実施形態では、ヒトCRBNの断片をコードする核酸配列は、安定して染色体に組み込まれる。いくつかの実施形態では、核酸は、マウス−ヒトキメラCRBN遺伝子を含む。特定の実施形態では、核酸配列は、ヒトCRBNアイソフォーム1のコドン24のグルタミン酸で開始し、ヒトCRBNアイソフォーム1の最終コドンで終わるポリペプチドを含むヒトCRBNの断片をコードする。他の実施形態では、核酸配列は、ヒトCRBNアイソフォーム2のコドン23のグルタミン酸で開始し、ヒトCRBNアイソフォーム2の最終コドンで終わるポリペプチドを含むヒトCRBNの断片をコードする。一実施形態では、全長ヒトCRBNタンパク質をコードする核酸配列は、配列番号5を含む。別の実施形態では、全長ヒトCRBNタンパク質をコードする核酸配列は、配列番号6を含む。一実施形態では、ヒトCRBNタンパク質の断片をコードする核酸配列は、配列番号7を含む。別の実施形態では、ヒトCRBNまたはその断片をコードする核酸配列を包含する標的化構築物は、配列番号8を含む。一実施形態では、トランスジェニックマウスは、全長ヒトCRBNを発現する。さらに別の実施形態では、トランスジェニックマウスは、ヒトCRBNの断片を発現する。
(a)この化合物をトランスジェニックマウスに投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;及び
(d)このバイオマーカーのレベルをバイオマーカーのベースレベルと比較すること;
を包含し、ここで
このバイオマーカーはCRBN関連タンパク質(CAP)である方法が提供される。
(a)このトランスジェニックマウスに第1の化合物及び第2の化合物を投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;ならびに
(d)このバイオマーカーのレベルをバイオマーカーのベースレベルと比較すること;を包含し、ここでこのバイオマーカーはCAPである方法が提供される。
(a)この化合物をトランスジェニックマウスに投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;及び
(d)このバイオマーカーのレベルに基づいて化合物の投与量及び/またはスケジュールを調節すること;を包含し、
ここで、このバイオマーカーがCAPである、方法が提供される。
本明細書で提供される方法は、部分的に、マウスE3ユビキチンリガーゼ複合体が、複合体の他のヒト化サブユニットを必要とすることなくヒトCRBNによって活性化され得るという発見に基づく。
「ヒトセレブロン」、「ヒトCRBN」または「hCRBN」という用語は、ポリペプチド(「ポリペプチド」、「ペプチド」及び「タンパク質」は本明細書では互換的に使用される)であって、ヒトCRBNタンパク質のアミノ酸配列(例えば、以下のアミノ酸配列を有するヒトCRBNアイソフォーム1、GenBankアクセッション番号NP_057386:MAGEGDQQDAAHNMGNHLPLLPAESEEEDEMEVEDQDSKEAKKPNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPQVMMILIPGQTLPLQLFHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPSNPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTIPDTEDEISPDKVILCL(配列番号1);または以下のアミノ酸配列を有する、ヒトCRBNアイソフォーム2、GenBankアクセッション番号NP_001166953:MAGEGDQQDAAHNMGNHLPLLPESEEEDEMEVEDQDSKEAKKPNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPQVMMILIPGQTLPLQLFHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPSNPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTIPDTEDEISPDKVILCL(配列番号2)、その各々は、その全体が参照によって本明細書に援用される)、及び関連のポリペプチド、例としては、そのSNPバリアントを含むポリペプチドを指す。関連のヒトCRBNポリペプチドとしては、対立遺伝子バリアント(例えば、SNPバリアント)、スプライスバリアント、断片、誘導体、置換バリアント、欠失バリアント、挿入バリアント、融合ポリペプチド、及び種間相同体が挙げられ、これは特定の実施形態では、ヒトCRBN活性を保持するか、及び/または抗hCRBN免疫応答を生成するに十分である。
MAGEGDQQDAAHNMGNHLPLLPDSEDEDDEIEMEVEDQDSKEARKPNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPEVLMILIPGQTLPLQLSHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQEFGIEVVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQVFPSKPISWEDQYSCKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPENPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKASNLNLIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTIPETEDEISPDKVILCL(配列番号3);または以下のアミノ酸配列を有するマウスCRBNアイソフォーム2、GenBankアクセッション番号NP_780566.1:MAGEGDQQDAAHNMGNHLPLLPADSEDEDDEIEMEVEDQDSKEARKPNIINFDTSLPTSHTYLGADMEEFHGRTLHDDDSCQVIPVLPEVLMILIPGQTLPLQLSHPQEVSMVRNLIQKDRTFAVLAYSNVQEREAQFGTTAEIYAYREEQEFGIEVVKVKAIGRQRFKVLELRTQSDGIQQAKVQILPECVLPSTMSAVQLESLNKCQVFPSKPISWEDQYSCKWWQKYQKRKFHCANLTSWPRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPENPIDFSYRVAACLPIDDVLRIQLLKIGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETLTVYKASNLNLIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTATKKDMSPQKFWGLTRSALLPTIPETEDEISPDKVILCL(配列番号4)、これらの各々は、その全体が参照により本明細書に組み込まれる)、及び関連ポリペプチド(そのSNPバリアントを含む)を含む、ポリペプチドを指す。関連するマウスCRBNポリペプチドとしては、特定の実施形態では、マウスCRBN活性を保持するか、及び/または抗mCRBN免疫応答を生成するのに十分である、対立遺伝子バリアント(例えば、SNPバリアント)、スプライスバリアント、断片、誘導体、置換バリアント、欠失バリアント、挿入バリアント、融合ポリペプチド及び種間相同体が挙げられる。
2つの核酸配列の文脈における「配列同一性」または「同一性」とは、特定の比較ウィンドウにわたって最大の対応のために整列される場合に同じであり、付加、欠失及び置換を考慮し得る2つの配列中の残基を指す。当業者は、比較される配列の全長にわたって最大のアラインメントを達成するために必要な任意のアルゴリズムを含む、配列を整列させるための適切なパラメーターを決定し得る。
Sambrook et al.,Molecular Cloning:A Laboratory Manual(2d ed.1989);Glover,ed.,DNA Cloning,Volumes I and II(1985);Gait,ed.,Oligonucleotide Synthesis(1984);Hames & Higgins,eds.,Nucleic Acid Hybridization(1984);Hames & Higgins,eds.,Transcription and Translation(1984);Freshney,ed.,Animal Cell Culture:Immobilized Cells and Enzymes(IRL Press,1986);Immunochemical Methods in Cell and Molecular Biology(Academic Press,London);Scopes,Protein Purification:Principles and Practice(Springer Verlag,N.Y.,2d ed.1987);及びWeir & Blackwell,eds.,Handbook of Experimental Immunology,Volumes I−IV(1986)。
特定の実施形態では、トランスジェニック動物は、トランスジェニック非ヒト哺乳動物、例えば、ウシ、ブタ、ヤギ、ウマ、げっ歯類(例えば、ラット、マウス、またはハムスター)などである。いくつかの実施形態では、トランスジェニック動物は、トランスジェニック齧歯類、例えば、ラット、マウス、ハムスターなどである。特定の実施形態では、トランスジェニック動物は、トランスジェニックマウスである。
atggccggcg aaggagatca gcaggacgct gcgcacaaca tgggcaacca cctgccgctc ctgcctgcag agagtgagga agaagatgaa atggaagttg aagaccagga tagtaaagaa gccaaaaaac caaacatcat aaattttgac accagtctgc cgacatcaca tacataccta ggtgctgata tggaagaatt tcatggcagg actttgcacg atgacgacag ctgtcaggtg attccagttc ttccacaagt gatgatgatc ctgattcccg gacagacatt acctcttcag ctttttcacc ctcaagaagt cagtatggtg cggaatttaa ttcagaaaga tagaaccttt gctgttcttg catacagcaa tgtacaggaa agggaagcac agtttggaac aacagcagag atatatgcct atcgagaaga acaggatttt ggaattgaga tagtgaaagt gaaagcaatt ggaagacaaa ggttcaaagt ccttgagcta agaacacagt cagatggaat ccagcaagct aaagtgcaaa ttcttcccga atgtgtgttg ccttcaacca tgtctgcagt tcaattagaa tccctcaata agtgccagat atttccttca aaacctgtct caagagaaga ccaatgttca tataaatggt ggcagaaata ccagaagaga aagtttcatt gtgcaaatct aacttcatgg cctcgctggc tgtattcctt atatgatgct gagaccttaa tggacagaat caagaaacag ctacgtgaat gggatgaaaa tctaaaagat gattctcttc cttcaaatcc aatagatttt tcttacagag tagctgcttg tcttcctatt gatgatgtat tgagaattca gctccttaaa attggcagtg ctatccagcg acttcgctgt gaattagaca ttatgaataa atgtacttcc ctttgctgta aacaatgtca agaaacagaa ataacaacca aaaatgaaat attcagttta tccttatgtg ggccgatggc agcttatgtg aatcctcatg gatatgtgca tgagacactt actgtgtata aggcttgcaa cttgaatctg ataggccggc cttctacaga acacagctgg tttcctgggt atgcctggac tgttgcccag tgtaagatct gtgcaagcca tattggatgg aagtttacgg ccaccaaaaa agacatgtca cctcaaaaat tttggggctt aacgcgatct gctctgttgc ccacgatccc agacactgaa gatgaaataa gtccagacaa agtaatactt tgcttgtaa(配列番号5)。いくつかの実施形態では、この全長ヒトCRBNアイソフォーム1のcDNAは、マウス染色体に安定に組み込まれる。
atggccggcg aaggagatca gcaggacgct gcgcacaaca tgggcaacca cctgccgctc ctgcctgaga gtgaggaaga agatgaaatg gaagttgaag accaggatag taaagaagcc aaaaaaccaa acatcataaa ttttgacacc agtctgccga catcacatac atacctaggt gctgatatgg aagaatttca tggcaggact ttgcacgatg acgacagctg tcaggtgatt ccagttcttc cacaagtgat gatgatcctg attcccggac agacattacc tcttcagctt tttcaccctc aagaagtcag tatggtgcgg aatttaattc agaaagatag aacctttgct gttcttgcat acagcaatgt acaggaaagg gaagcacagt ttggaacaac agcagagata tatgcctatc gagaagaaca ggattttgga attgagatag tgaaagtgaa agcaattgga agacaaaggt tcaaagtcct tgagctaaga acacagtcag atggaatcca gcaagctaaa gtgcaaattc ttcccgaatg tgtgttgcct tcaaccatgt ctgcagttca attagaatcc ctcaataagt gccagatatt tccttcaaaa cctgtctcaa gagaagacca atgttcatat aaatggtggc agaaatacca gaagagaaag tttcattgtg caaatctaac ttcatggcct cgctggctgt attccttata tgatgctgag accttaatgg acagaatcaa gaaacagcta cgtgaatggg atgaaaatct aaaagatgat tctcttcctt caaatccaat agatttttct tacagagtag ctgcttgtct tcctattgat gatgtattga gaattcagct ccttaaaatt ggcagtgcta tccagcgact tcgctgtgaa ttagacatta tgaataaatg tacttccctt tgctgtaaac aatgtcaaga aacagaaata acaaccaaaa atgaaatatt cagtttatcc ttatgtgggc cgatggcagc ttatgtgaat cctcatggat atgtgcatga gacacttact gtgtataagg cttgcaactt gaatctgata ggccggcctt ctacagaaca cagctggttt cctgggtatg cctggactgt tgcccagtgt aagatctgtg caagccatat tggatggaag tttacggcca ccaaaaaaga catgtcacct caaaaatttt ggggcttaac gcgatctgct ctgttgccca cgatcccaga cactgaagat gaaataagtc cagacaaagt aatactttgc ttgtaa(配列番号6)。いくつかの実施形態では、全長ヒトCRBNアイソフォーム2のcDNAは、マウス染色体に安定に組み込まれる。
ag agagtgagga agaagatgaa atggaagttg aagaccagga tagtaaagaa gccaaaaaac caaacatcat aaattttgac accagtctgc cgacatcaca tacataccta ggtgctgata tggaagaatt tcatggcagg actttgcacg atgacgacag ctgtcaggtg attccagttc ttccacaagt gatgatgatc ctgattcccg gacagacatt acctcttcag ctttttcacc ctcaagaagt cagtatggtg cggaatttaa ttcagaaaga tagaaccttt gctgttcttg catacagcaa tgtacaggaa agggaagcac agtttggaac aacagcagag atatatgcct atcgagaaga acaggatttt ggaattgaga tagtgaaagt gaaagcaatt ggaagacaaa ggttcaaagt ccttgagcta agaacacagt cagatggaat ccagcaagct aaagtgcaaa ttcttcccga atgtgtgttg ccttcaacca tgtctgcagt tcaattagaa tccctcaata agtgccagat atttccttca aaacctgtct caagagaaga ccaatgttca tataaatggt ggcagaaata ccagaagaga aagtttcatt gtgcaaatct aacttcatgg cctcgctggc tgtattcctt atatgatgct gagaccttaa tggacagaat caagaaacag ctacgtgaat gggatgaaaa tctaaaagat gattctcttc cttcaaatcc aatagatttt tcttacagag tagctgcttg tcttcctatt gatgatgtat tgagaattca gctccttaaa attggcagtg ctatccagcg acttcgctgt gaattagaca ttatgaataa atgtacttcc ctttgctgta aacaatgtca agaaacagaa ataacaacca aaaatgaaat attcagttta tccttatgtg ggccgatggc agcttatgtg aatcctcatg gatatgtgca tgagacactt actgtgtata aggcttgcaa cttgaatctg ataggccggc cttctacaga acacagctgg tttcctgggt atgcctggac tgttgcccag tgtaagatct gtgcaagcca tattggatgg aagtttacgg ccaccaaaaa agacatgtca cctcaaaaat tttggggctt aacgcgatct gctctgttgc ccacgatccc agacactgaa gatgaaataa gtccagacaa agtaatactt tgcttgtaa(配列番号7)。いくつかの実施形態では、ヒトCRBNアイソフォーム1のcDNAの断片は、マウス染色体に安定に組み込まれる。他の実施形態では、ヒトCRBNアイソフォーム2のcDNAの断片は、マウス染色体に安定に組み込まれる。
aagaacagctcacacttgatagaataccacttctagaaagtagcgttgtgttttgtttcttcagactttcatctctgcccttggcagcatcatgttatcaggtggatcagcttagctttcatttcatttcaaaaaaaaaagtgcaggtagagttcttaagatatctccttttgccaggcagtggtggcgcactcctttaatcccagcacttgggaggcagaggcaggcagatttctgagttcgaggccagcctggtctacagagtgagttccaggacagccagggctacatagagaaaccctgtctccaaaaactcgaaaaacagaaaagaaaagaaaaaaaaaaaagacatctcctttaaaatgtattttctttgggccaactttatttttaaattgagaatgacaaagcgatgttttatgaaaaataattgcaaacatttcacgtttaaatatgacggtgagccaggttttaatggtattttttttcccagtttcattaacagacctttcttgcctgcttgtgttttccttgctttctttttcacagagaaactttgtagctaaagtctgaaagaacctcatagattactttgttcaagccttcattgttttttttttcaaatgaaaaaacagctttaatcaattggaattcattgtgtaaggtgtcaggattagtagtgatggagaagataagactcatccatgcaggagatgggcctaattcagccacgtcagtcgttaggctggacctagtgatctgctttccaaccgtgtacggtgtaactgcggggcaggggcgagggggtttacagagaaggaagctggcggctgtttctgaccagaaatcaaggggaacatcagcccctgggtcaggctgactgtacgtacccttgatgtgcggtgaggaataggcgttgtccctagcagaactctaatagagaatgacatctattccctattgagggatgctgtgtaaagtcctgataaggaagacagaacatccagcatgcgtgtaccacaggcagcaaaggagccatacctaaatatagcatggtgtcctggaggggtaacaggaaatggagaatagctgaaaatcaaaggcaatccaaataagataaggcatttagttaacagtaatgtgccaatatcgacgacttagttgtcacaagaataccagatgcatggaccatgctaacaatggaggaagatagtcttggcatgctagaattctatttttccaacattccaggaaatcttaaagtgtcctaagatagttgattgttaaaaacagggaaaaaagaaaggaaaggaaaagaaaggaaaaggcgccatgacagaaagagcacagacccagcctctgccgctgtctctgcacagctttccttttaagagtgtctttcttcaattcagggtgtgtgaatggaaccagaactgacttgcttttttcttttctttttttttttttttaatgaatctcattttttccctctattattctccttcagcagagagtgaggaagaagatgaaatggaagttgaagaccaggatagtaaagaagccaaaaaaccaaacatcataaattttgacaccagtctgccgacatcacatacatacctaggtgctgatatggaagaatttcatggcaggactttgcacgatgacgacagctgtcaggtgattccagttcttccacaagtgatgatgatcctgattcccggacagacattacctcttcagctttttcaccctcaagaagtcagtatggtgcggaatttaattcagaaagatagaacctttgctgttcttgcatacagcaatgtacaggaaagggaagcacagtttggaacaacagcagagatatatgcctatcgagaagaacaggattttggaattgagatagtgaaagtgaaagcaattggaagacaaaggttcaaagtccttgagctaagaacacagtcagatggaatccagcaagctaaagtgcaaattcttcccgaatgtgtgttgccttcaaccatgtctgcagttcaattagaatccctcaataagtgccagatatttccttcaaaacctgtctcaagagaagaccaatgttcatataaatggtggcagaaataccagaagagaaagtttcattgtgcaaatctaacttcatggcctcgctggctgtattccttatatgatgctgagaccttaatggacagaatcaagaaacagctacgtgaatgggatgaaaatctaaaagatgattctcttccttcaaatccaatagatttttcttacagagtagctgcttgtcttcctattgatgatgtattgagaattcagctccttaaaattggcagtgctatccagcgacttcgctgtgaattagacattatgaataaatgtacttccctttgctgtaaacaatgtcaagaaacagaaataacaaccaaaaatgaaatattcagtttatccttatgtgggccgatggcagcttatgtgaatcctcatggatatgtgcatgagacacttactgtgtataaggcttgcaacttgaatctgataggccggccttctacagaacacagctggtttcctgggtatgcctggactgttgcccagtgtaagatctgtgcaagccatattggatggaagtttacggccaccaaaaaagacatgtcacctcaaaaattttggggcttaacgcgatctgctctgttgcccacgatcccagacactgaagatgaaataagtccagacaaagtaatactttgcttgtaagtgcacctagagctcgctgatcagcctcgactgtgccttctagttgccagccatctgttgtttgcccctcccccgtgccttccttgaccctggaaggtgccactcccactgtcctttcctaataaaatgaggaaattgcatcgcattgtctgagtaggtgtcattctattctggggggtggggtggggcaggacagcaagggggaggattgggaagacaatagcaggcatgctggggatgcggtgggctctatggcttctgaggcggaaagaaccagctggggctcgactagagcttgcggaacccttcgtatgtggtttagtcattgagcaaatgcagtatgcggacctttatctatggctggaatttggtaccttttgctagcataacttcgtatagcatacattatacgaagttatcctaggtaattctaccgggtaggggaggcgcttttcccaaggcagtctggagcatgcgctttagcagccccgctgggcacttggcgctacacaagtggcctctggcctcgcacacattccacatccaccggtaggcgccaaccggctccgttctttggtggccccttcgcgccaccttctactcctcccctagtcaggaagttcccccccgccccgcagctcgcgtcgtgcaggacgtgacaaatggaagtagcacgtctcactagtctcgtgcagatggacagcaccgctgagcaatggaagcgggtaggcctttggggcagcggccaatagcagctttgctccttcgctttctgggctcagaggctgggaaggggtgggtccgggggcgggctcaggggcgggctcaggggcggggcgggcgcccgaaggtcctccggaggcccggcattctgcacgcttcaaaagcgcacgtctgccgcgctgttctcctcttcctcatctccgggcctttcgacctgcagcctgttgacaattaatcatcggcatagtatatcggcatagtataatacgacaaggtgaggaactaaaccagatctgccaccatgattgaacaagatggattgcacgcaggttctccggccgcttgggtggagaggctattcggctatgactgggcacaacagacaatcggctgctctgatgccgccgtgttccggctgtcagcgcaggggcgcccggttctttttgtcaagaccgacctgtccggtgccctgaatgaactgcaggacgaggcagcgcggctatcgtggctggccacgacgggcgttccttgcgcagctgtgctcgacgttgtcactgaagcgggaagggactggctgctattgggcgaagtgccggggcaggatctcctgtcatctcaccttgctcctgccgagaaagtatccatcatggctgatgcaatgcggcggctgcatacgcttgatccggctacctgcccattcgaccaccaagcgaaacatcgcatcgagcgagcacgtactcggatggaagccggtcttgtcgatcaggatgatctggacgaagagcatcaggggctcgcgccagccgaactgttcgccaggctcaaggcgcgcatgcccgacggcgaggatctcgtcgtgacccatggcgatgcctgcttgccgaatatcatggtggaaaatggccgcttttctggattcatcgactgtggccggctgggtgtggcggaccgctatcaggacatagcgttggctacccgtgatattgctgaagagcttggcggcgaatgggctgaccgcttcctcgtgctttacggtatcgccgctcccgattcgcagcgcatcgccttctatcgccttcttgacgagttcttctgacttaagaacttgtttattgcagcttataatggttacaaataaagcaatagcatcacaaatttcacaaataaagcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatcttatcatgtctgcaattgataacttcgtatagcatacattatacgaagttatgaattcttttctcgagcctaagtgcagggagccacactaggggactagtgcaggggactgactagagggttcctgcatattcgctgaccctagaatccgtgcatgagaacagacttattttccagtgcatagcatgtaattttagaaatggaagccgtgtcgtactatatcctcatgtgattcttgactattttctaatatgtaagctgatatgtaaacattaaagctaacatatagctttatgtttaaacttatcttgggagggactctttgaggaattgtcttcctctgaagggttctgctagtaactgagccattaagtgttcttaatgttgtttcagaactgctgggatgtg
gggcggtattataggtactaaaattctgtcctatgctttgtcagttttggacatagaggagttttggtgaaaatattttgaattacaaaataatgatcgattcttgataaaaattgggagttctaataggaaatactagatcaaaaattagagtttgatggaggcatgcttatataacagattatttaaataaacatgtgctctgtttagtgttttcctctgctttattctttagtaggttgacgtgtagtaagtgtgtgtcttgactctgtgctcttgagtagtacctgggagctgatatggaggagttccacgggagaactttgcatgacgacgacagctgccaggtgatcccagtccttcctgaggtgctgatgatcctgattcctgggcagacactcccactgcagctctctcacccacaggaagtcagcatggtgcggaacttaatccagaaagacaggacctttgcagtccttgcatacaggtaagagattagacagatctgcttaccaccctgccaaagtcagtgcgacagctaaagccaacggggatttgcagatactggacaggagtgtgaagcaaacggtcttgtgtcacattttcagtgtttcgctgtttttacagtgtagctgtgtttggctcttgaaaaacttccactcacttaatggaaaacctccctgttcagaactgtctttatttaaaaatagctaagttttaaaattttcaataaaggttacttttctaaagtgaagctgttcttcagtagcctgtggcaaatgagggaaccgtggtggaggcaggaaatggaaacaggaaacctcccatcacccccgctgaccctcccctcagacagtcacagtgctgccagttagtgcgaccatcattgcctgccaaagtgaaaggatgctcattttgtgaaataacgatttaaaacttcttagcactggttatctcagtgaagcctaaaagtctacctttattctaaaatatgctgtttgccttccggggccttgtgtgtcagcttcctagtgagggttagctgctgtaattgtcacagtgtttgcccgatctgtgtcgcttttgccacctttacataattatgagccagagctgaaaactctgtccatttttgtctttgaagtaatgtgcaagaaaggg(配列番号8)。いくつかの実施形態では、標的化構築物は、マウス染色体に安定に組み込まれる。
別の態様では、(a)ヒトCRBNまたはその断片をコードする核酸配列を含むポリヌクレオチド構築物をマウス卵に導入すること、及び;(b)このマウス卵を雌性マウスに移入することを包含する、ヒトCRBNを発現するトランスジェニックマウスを作製するための方法が本明細書で提供される。本明細書では、また、(a)ヒトCRBNまたはその断片をコードする核酸配列を含むポリヌクレオチド構築物をマウス胚に導入すること;及び(b)このマウス胚を雌性マウスに移入すること、を包含する、ヒトCRBNを発現するトランスジェニックマウスを産生するための方法も提供される。本明細書ではまた、(a)ヒトCRBNまたはその断片をコードする核酸配列を含むポリヌクレオチド構築物をマウス胚性幹(ES)細胞に導入すること;及び(b)このマウスES細胞を雌性マウスに移入することを包含する、ヒトCRBNを発現するトランスジェニックマウスを作製する方法も提供される。特定の実施形態では、核酸配列は、ヒトCRBNをコードする。特定の実施形態では、ヒトCRBNをコードする核酸配列は、卵、胚またはES細胞の染色体に安定に組み込まれる。他の実施形態では、核酸配列は、ヒトCRBNの断片をコードする。特定の実施形態では、ヒトCRBNの断片をコードする核酸配列は、卵、胚またはES細胞の染色体に安定に組み込まれる。特定の実施形態では、核酸配列は、ヒトCRBNアイソフォーム1のコドン24のグルタミン酸で開始し、ヒトCRBNアイソフォーム1の最終コドンで終わるポリペプチドを含むヒトCRBNの断片をコードする。特定の実施形態では、核酸配列は、ヒトCRBNアイソフォーム2のコドン23のグルタミン酸で開始し、ヒトCRBNアイソフォーム2の最終コドンで終わるポリペプチドを含むヒトCRBNの断片をコードする。1つの実施形態では、全長ヒトCRBNタンパク質をコードする核酸配列は、配列番号5を含む。別の実施形態では、全長ヒトCRBNタンパク質をコードする核酸配列は、配列番号6を含む。一実施形態では、ヒトCRBNタンパク質の断片をコードする核酸配列は、配列番号7を含む。別の実施形態では、ヒトCRBNまたはその断片をコードする核酸配列を包含する標的化構築物は、配列番号8を含む。
ヒトCRBNを発現するトランスジェニックマウスは、限定するものではないが、有効性、特異性、毒性、薬物動態学、薬力学、作用機序、投与レジメンの最適化、及びそのような疾患のための他の治療薬との併用療法の研究を含む、様々な疾患(例えば、がん)の処置における化合物の評価などの様々な研究のために使用してもよい。
ヒトCRBNを発現するトランスジェニックマウスを用いるこれらの研究の多くにおいて、バイオマーカーは研究者にとって重要な情報を提供し、安全かつ有効な治療法の設計及び開発においてそれらを導く。特定のバイオマーカーの検出可能な増減は、所与の治療(例えば、化合物、またはその立体異性体もしくは立体異性体の混合物、互変異性体、薬学的に許容される塩、溶媒和物、同位体置換体、プロドラッグ、水和物、共結晶、包接体またはその多形体)に応答する特定の疾患(例えば、がん)を有する対象において観察され、これらのバイオマーカーのレベルは、処置に対する対象の反応性をモニターするために使用され得る。
本明細書で提供される様々な化合物は、1つ以上のキラル中心を含み、エナンチオマーの混合物(例えば、ラセミ混合物)またはジアステレオマーの混合物として存在し得る。本明細書で提供される方法は、そのような化合物の立体異性的に純粋な形態ならびにそれらの形態の混合物の使用を包含する。例えば、特定の化合物のエナンチオマーの等量または不等量を含む混合物は、本明細書で提供される方法において使用され得る。これらの異性体は、キラルカラムまたはキラル分割剤などの標準的技術を使用して、非対称的に合成されても、または分割されてもよい。Jacques et al.,Enantiomers,Racemates and Resolutions(Wiley−Interscience,New York,1981);Wilen et al.,Tetrahedron 1977,33:2725−2736;Eliel,Stereochemistry of Carbon Compounds(McGraw−Hill,NY,1962);Wilen,Tables of Resolving Agents and Optical Resolutions,p.268(Eliel,ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972)を参照のこと。
以下の構造を有する、3−(5−アミノ−2−メチル−4−オキソ−4H−キナゾリン−3−イル)−ピペリジン−2,6−ジオン(「化合物A」):
以下の構造を有する、3−(4−((4−(モルホリノメチル)ベンジル)オキシ)−1−オキソイソインドリン−2−イル)ピペリジン−2,6−ジオン(「化合物B」):
以下の構造を有する、1−(3−クロロ−4−メチルフェニル)−3−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)尿素(」化合物C」):
以下の構造を有する、2−(4−クロロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物D」):
以下の構造を有する、2−(4−フルオロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物E」):
またはその立体異性体もしくは立体異性体の混合物、互変異性体、薬学的に許容される塩、溶媒和物、同位体置換体、プロドラッグ、水和物、共結晶、包接体もしくは多形体、からなる群より選択される。
別の態様では、本明細書において、ヒトCRBNまたはその断片を発現するトランスジェニックマウスにおいて、化合物の投与量及び/またはスケジュールを最適化するための方法であって:
(a)この化合物をトランスジェニックマウスに投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;及び
(d)このバイオマーカーのレベルに基づいて化合物の投与量及び/またはスケジュールを調節すること;
を包含し、ここでこのバイオマーカーがCRBN関連タンパク質(CAP)である方法が提供される。
以下の構造を有する3−(4−((4−(モルホリノメチル)ベンジル)オキシ)−1−オキソイソインドリン−2−イル)ピペリジン−2,6−ジオン(「化合物B」):
以下の構造を有する、1−(3−クロロ−4−メチルフェニル)−3−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)尿素(「化合物C」):
以下の構造を有する、2−(4−クロロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物D」):
以下の構造を有する、2−(4−フルオロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物E」):
またはその立体異性体もしくは立体異性体の混合物、互変異性体、薬学的に許容される塩、溶媒和物、同位体置換体、プロドラッグ、水和物、共結晶、包接体もしくは多形体、からなる群より選択される化合物である。
(a)ヒトCRBNを発現するトランスジェニックマウスに化合物を投与すること;
(b)トランスジェニックマウスの身体的外観を観察すること;及び
(c)ヒトCRBNを発現するトランスジェニックマウスの身体的外観が標準を満たすかまたは満たさない場合、化合物の投与量及び/またはスケジュールを調節すること、を包含する方法も提供される。
(a)この化合物をトランスジェニックマウスに投与すること;
(b)このトランスジェニックマウスの生物学的パラメーターを測定すること;ならびに
(c)CRBNを発現するトランスジェニックマウスの生物学的パラメーターが標準を満たすかまたは満たさない場合、化合物の投与量及び/またはスケジュールを調節すること、を包含する方法が提供される。
別の態様では、本明細書において、ヒトCRBNまたはその断片を発現するトランスジェニックマウスにおける化合物の効果を評価するための方法であって、
(a)この化合物をトランスジェニックマウスに投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;及び
(d)このバイオマーカーのレベルをバイオマーカーのベースレベルと比較することを包含し、ここでバイオマーカーがCAPである方法が提供される。
(a)このトランスジェニックマウスに第1の化合物及び第2の化合物を投与すること;
(b)このトランスジェニックマウスから試料を得ること;
(c)この試料中のバイオマーカーのレベルを測定すること;及び
(d)このバイオマーカーのレベルをバイオマーカーのベースレベルと比較すること;を包含し、ここでこのバイオマーカーがCAPである方法が提供される。
以下の構造を有する、3−(4−((4−(モルホリノメチル)ベンジル)オキシ)−1−オキソイソインドリン−2−イル)ピペリジン−2,6−ジオン(「化合物B」):
以下の構造を有する、1−(3−クロロ−4−メチルフェニル)−3−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)尿素(「化合物C」):
:
以下の構造を有する、2−(4−クロロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物D」):
以下の構造を有する、2−(4−フルオロフェニル)−N−((2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−5−イル)メチル)−2,2−ジフルオロアセトアミド(「化合物E」):
またはそれらの薬学的に許容される塩、溶媒和物、立体異性体、同位体置換体、プロドラッグ、水和物、共結晶、包接体もしくは多形体からなる群より選択される化合物である。
本明細書で提供される様々な方法の特定の実施形態では、化合物または化合物の組み合わせの効果は、抗原特異的T細胞殺傷に対する効果である。T細胞媒介細胞傷害性は、ナイーブT細胞に種々の特異的抗原をもたらす抗原提示細胞(APC)によって誘導され得る。APCの非限定的な例としては、樹状細胞(DC)、マクロファージ、特定のB細胞、及び特定の活性化上皮細胞が挙げられる。次いで、活性化された細胞傷害性T細胞は、その表面に特異的抗原(例えば、腫瘍抗原)を有する標的細胞(例えば、腫瘍細胞)を殺傷する。インビボまたはインビトロでの抗原特異的T細胞殺傷を評価するための様々な方法は、科学文献に開示されている(例えば、自己樹状細胞でパルスされた乳房腫瘍細胞溶解物により誘導されるT細胞応答のインビトロ分析(in vitro analysis of T−cell responses induced by breast tumor cell lysate pulsed with autologous dendritic cells))。Delirezh et al.、Advances in Biosci.Biotechnol.2012、3:126−136を参照のこと。
以下の実施例は、他に詳細に記載されている場合を除いて、当業者に周知であり日常的な標準的な技術を用いて行われる。この実施例は単なる例示であることが意図される。
ヒトCRBNアイソフォーム1及びマウスCRBNアイソフォーム2(ヒトCRBNアイソフォーム1に対応する)の最初の23アミノ酸は同一である。これらの23個のアミノ酸は、ヒトまたはマウスCRBN遺伝子のエキソン1によってコードされる。別のスプライシング機構は、第23番目のアミノ酸を除去して、ヒトCRBNアイソフォーム2またはマウスCRBNアイソフォーム1を生成する(これはそれぞれヒトCRBNアイソフォーム1またはマウスCRBNアイソフォーム2よりも1アミノ酸短い)。従って、マウスエキソン1/イントロン1/エキソン2スプライシングが維持され得る。ノックインの戦略は、エキソン2で開始する、CRBNをコードするヒトcDNAを挿入することである。これは、cDNAのインビボ発現に重要なイントロンを含むことにより、内因性マウスプロモーターからのヒトcDNAの十分な発現を確実にする助けとなるはずである。ヒトCRBNのcDNAコード配列の後のポリ(A)配列は、転写産物を終結させ、マウス遺伝子の任意のさらなるスプライシングまたは発現を破壊する。宿主マウスにおける選択的スプライシング機構は、トランスジェニックマウスにおいてヒトCRBNアイソフォーム1及びヒトCRBNアイソフォーム2を生成することができるであろう。エキソン3は、エキソン1とはフレーム外であり、そのため異常なスプライシングは機能的CRBNタンパク質を生じないであろう。
3つのXTN(商標)TALENを、ネオマイシンカセット挿入部位を標的化して標的化を増強するように設計した。XTN(商標)TALEN 1は、
TATGCGGACCTTTATCTAtggctggaatttcctaAGTGCAGGGAGCCACA(配列番号9)という核酸配列を標的する。
XTN(商標)TALEN 2は、TGCAGTATGCGGACCTTtatctatggctggaatTTCCTAAGTGCAGGGA(配列番号10)という核酸配列を標的とする。XTN(商標)TALEN 3は、TCTGCCAACCTCACATacagtatgtggtttaGTCATTGAGCAAATGCA(配列番号11)の核酸配列を標的とする。
C57BL/6NTac JM8 ES細胞を、ドナーベクターCRBN KI Vector−V2−pUC及びXTN(商標)TALEN 2を用いてエレクトロポレーションした。正確な5’及び3’標的化を検出するために、プライマーを用いた標的化のために24のESクローンをスクリーニングした。5’及び3’標的を検出するためのPCRプライマーを表1に列挙する。
表1.5’及び3’標的を検出するためのPCRプライマー
2つのESクローン(D2及びE1)を、C57BL/6NTac芽球に注入した。3.5日齢のマウス胚(胚盤胞)を、クローンD2及びE1由来のES細胞の標準的な注入方法に用いた。次いで、注入された胚盤胞を、偽妊娠雌性マウスに移植した。キメラは、Nnt遺伝子型またはコート色によって生まれ、確認された。クローンE1は、最高レベルのキメラ現象をもたらした。これらのキメラは、生殖系列伝達のために繁殖するように選択した。
ネオマイシン耐性カセットの欠失を達成し、生殖系列伝達を決定するために、クローンE1由来のキメラを、Creリコンビナーゼデレター(deleter)マウス(ROSA26座から発現されたCre)に交配させた。子孫は、ヒトcDNA挿入物に特異的なPCRプライマーを用いて評価した。3匹の仔(2匹の雌及び1匹の雄)をPCRによって同定し、ヒトcDNA−bGH pA、1つのloxP部位を含み、かつネオマイシンカセットを含まないことを配列で確認した。
ヒトCRBN遺伝子の生殖系列伝達を有する上記の2つのヘテロ接合性雌性マウスを、増殖育種のために使用した。これは、ヒトCRBN遺伝子を発現する安定した系統のマウスを確保し確立することであった。目標は、ヒトCRBN遺伝子とホモ接合マウスのコホートを確立すること、及びCreリコンビナーゼ対立遺伝子を削除することであった。雌性マウスを、非Cre C57BL/6NTacマウスと育種してCre遺伝子を除去し、ヘテロ接合性のヒトCRBNノックインマウスを作製した。ヘテロ接合ヒトCRBNノックインマウス間の交配によって、ホモ接合ヒトCRBNノックインマウスを産生した。
ヒトCRBN遺伝子についてホモ接合性のマウスを、他の遺伝的背景のマウス、例えばNSG/NOGマウス、Vk*myc多発性骨髄性モデル、Eu−v−abl/Eu−c−Myc(ウイルス接種+プリスチン)多発性骨髄腫モデル、Eu−c−Mycリンパ腫モデル、ヒトIKZF1/3トランスジェニックマウスなどと育種してもよい。これらの育種されたマウスは、限定するものではないが、異種移植の分析、抗腫瘍効果、及び免疫細胞効果を含むさらなる研究に有用である。
ヒトCRBNトランスジェニックマウスに由来する細胞、細胞株、組織または器官を使用して、化合物(例えば、サリドマイド、レナリドマイド、ポマリドマイド及びセクション5.4.2で提供される他の化合物などの免疫調節化合物)をインビトロまたはエキソビボで研究してもよい。ヒトCRBNトランスジェニックマウスを使用して、化合物(例えば、サリドマイド、レナリドマイド、ポマリドマイド、及びセクション5.4.2で提供される他の化合物などの免疫調節化合物)をインビボで研究してもよい。これらの研究には、限定するものではないが、結合アッセイ(例えば、CRBN結合アッセイ、CAP結合アッセイ)、標的タンパク質分解アッセイ、下流機能アッセイ、バイオマーカーアッセイ、プロテオミクス研究、毒性、薬物動態、薬力学、様々な疾患の処置の有効性、投与レジメン最適化、処置の特異性、併用療法、作用機序などが挙げられる。
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本明細書は、コンピュータ可読形式(CRF)の配列表のコピーとともに提出されている。2017年1月12日に作成され、サイズが31,899バイトである12827−974−228_SEQLIST.txtと名付けられたCRFは、配列表の紙のコピーと同一であり、その全体が参照により本明細書に組み込まれる。
Claims (81)
- トランスジェニックマウスであって、そのゲノムが、ヒトセレブロン(CRBN)またはその断片をコードする核酸を含み、ここで内因性マウスCRBNが、前記トランスジェニックマウスで発現されない、前記トランスジェニックマウス。
- 前記核酸が全長ヒトCRBNタンパク質をコードする、請求項1に記載のトランスジェニックマウス。
- 全長ヒトCRBNタンパク質をコードする前記核酸が、配列番号5または配列番号6を含む、請求項2に記載のトランスジェニックマウス。
- 前記核酸が、マウス−ヒトキメラCRBN遺伝子を含む、請求項1に記載のトランスジェニックマウス。
- 前記核酸が、ヒトCRBNアイソフォーム1のコドン24のグルタミン酸で開始し、ヒトCRBNアイソフォーム1の最終コドンで終わるポリペプチドを含む、ヒトCRBNタンパク質の断片をコードする、請求項1または4に記載のトランスジェニックマウス。
- 前記核酸が、ヒトCRBNアイソフォーム2のコドン23のグルタミン酸で開始し、ヒトCRBNアイソフォーム2の最終コドンで終わるポリペプチドを含む、ヒトCRBNタンパク質の断片をコードする、請求項1または4に記載のトランスジェニックマウス。
- ヒトCRBNの断片をコードする前記核酸が配列番号7を含む、請求項1、4、5または6のいずれか1項に記載のトランスジェニックマウス。
- ヒトCRBNの発現が、相同なマウスプロモーターによって制御される、請求項1〜7のいずれか1項に記載のトランスジェニックマウス。
- 前記核酸が、染色体に安定に組み込まれている、請求項1〜8のいずれか1項に記載のトランスジェニックマウス。
- ヒトCRBNまたはその断片をコードする核酸配列を含む、請求項1〜9のいずれか1項に記載のトランスジェニックマウスから得られた単離された細胞。
- ヒトCRBNまたはその断片をコードする核酸配列を含む、請求項1〜9のいずれか1項に記載のトランスジェニックマウスに由来する形質転換細胞株。
- ヒトCRBNまたはその断片をコードする核酸配列を含む、請求項1〜9のいずれか1項に記載のトランスジェニックマウスから得られた単離された組織。
- ヒトCRBNまたはその断片をコードする核酸配列を含む、請求項1〜9のいずれか1項に記載のトランスジェニックマウスから得られた単離器官。
- ヒトCRBNを発現するトランスジェニックマウスを作製する方法であって、
(a)ヒトCRBNまたはその断片をコードする核酸を含むポリヌクレオチド構築物をマウス卵、胚または胚性幹(ES)細胞に導入すること;及び
(b)ヒトCRBNまたはその断片をコードする核酸配列を有するマウス卵、胚またはES細胞を雌性マウスに移入することを包含する、前記方法。 - 前記核酸が、請求項2〜7のいずれか1項に記載のものである、請求項14に記載の方法。
- 前記ポリヌクレオチド構築物が、配列番号8の核酸配列を含む、請求項14または15に記載の方法。
- 雌性マウスを育種すること、ヒトCRBNまたはその断片を発現する子孫を選択することをさらに包含する、請求項14〜16のいずれか1項に記載の方法。
- ヒトCRBNまたはその断片を発現する子孫と遺伝的背景のマウスとを育種することをさらに包含する、請求項17に記載の方法。
- 前記遺伝的背景のマウスが、NSG/NOGマウスモデル、Vk*myc多発性骨髄腫マウスモデル、Eu−v−abl/Eu−c−Myc多発性骨髄腫マウスモデル、Eu−c−Mycリンパ腫マウスモデル、ヒトIKZF1トランスジェニックマウスモデル、及びヒトIKZF3トランスジェニックマウスモデルからなる群より選択される、請求項18に記載の方法。
- 遺伝的背景においてヒトCRBNを発現するトランスジェニックマウスを作製する方法であって、請求項1〜9のいずれか1項に記載のトランスジェニックマウスと前記遺伝的背景のマウスとを育種することを包含する、前記方法。
- 前記遺伝的背景のマウスが、NSG/NOGマウスモデル、Vk*myc多発性骨髄腫マウスモデル、Eu−v−abl/Eu−c−Myc多発性骨髄腫マウスモデル、Eu−c−Mycリンパ腫マウスモデル、ヒトIKZF1トランスジェニックマウスモデル、及びヒトIKZF3トランスジェニックマウスモデルからなる群より選択される、請求項20に記載の方法。
- 請求項14〜21のいずれか1項に記載の方法によって作製されたトランスジェニックマウス。
- ヒトCRBNまたはその断片を発現するトランスジェニックマウスにおいて、化合物の投与量及び/またはスケジュールを最適化する方法であって、
(a)前記化合物を前記トランスジェニックマウスに投与すること;
(b)前記トランスジェニックマウスから試料を得ること;
(c)前記試料中のバイオマーカーのレベルを測定すること;ならびに
(d)前記バイオマーカーのレベルに基づいて前記化合物の投与量及び/またはスケジュールを調節すること;を包含し、
ここで、前記バイオマーカーはCRBN関連タンパク質(CAP)である、前記方法。 - 前記トランスジェニックマウスが、請求項1〜9または22のいずれか1項に記載のトランスジェニックマウスである、請求項23に記載の方法。
- 前記バイオマーカーのレベルが前記バイオマーカーのベースレベルよりも高い場合、前記化合物の投与量及び/またはスケジュールが調整される、請求項23または24に記載の方法。
- 前記バイオマーカーのレベルが前記バイオマーカーのベースレベルより低い場合、前記化合物の投与量及び/またはスケジュールが調整される、請求項23または24に記載の方法。
- 前記バイオマーカーが、eRF3a、eRF3b、eRF3c、IKZF1、IKZF3、CK1a、PABP1、eRF1、BIP、eEF1α、PERK、GCN2、eIF2a、ATF4、ATF3、DDIT3、PPP1R15A、TNFRSF10B、GADD45A、TNFRSF1A、TNFRSF1B、FAS、FADD、IRE1、XBP1、SEC24D、DNAJB9、EDEM1、EDEM2、HYOU1、ATF6、HSPA5、カスパーゼ8、BID、カスパーゼ9、カスパーゼ7、カスパーゼ3、PARP、Mcl−1、BAD、CDKN1A、Myc、IRF4、IRF7、IFIT1、IFIT3、RIG−I、MDA−5、TBK1、IKKe、ZFP91、ZNF198、MVP、Parp4、Ron、PDE6D、TLR3、STAT1、STAT2、STAT3、IFNa、IFNb、OAS1、OAS2、OAS3、IFIT2、ISG15、ISG20、、IFI21、IFI35、IFI6、IFITM3、IFITM2WIZ、GBP2、GBP4、SELL、SNX20、KLF13、GBP1、MARCKS、SLAMF1、及びSASH1からなる群より選択される、請求項23〜26のいずれか1項に記載の方法。
- ヒトCRBNまたはその断片を発現するトランスジェニックマウスにおける化合物の効果を評価するための方法であって、
(a)前記化合物を前記トランスジェニックマウスに投与すること;
(b)前記トランスジェニックマウスから試料を得ること;
(c)前記試料中のバイオマーカーのレベルを測定すること;及び
(d)前記バイオマーカーのレベルをバイオマーカーのベースレベルと比較すること;を包含し、前記バイオマーカーはCAPである、前記方法。 - 前記トランスジェニックマウスが、請求項1〜9または22のいずれか1項に記載のトランスジェニックマウスである、請求項28に記載の方法。
- 前記バイオマーカーのベースレベルが、
(i)化合物が前記トランスジェニックマウスに投与されていない場合;または(ii)前記トランスジェニックマウスに対照化合物を投与する場合の前記バイオマーカーのレベルである、請求項28または29に記載の方法。 - ヒトCRBNまたはその断片を発現するトランスジェニックマウスにおける化合物の組み合せの効果を評価するための方法であって:
(a)前記トランスジェニックマウスに第1の化合物及び第2の化合物を投与すること;
(b)前記トランスジェニックマウスから試料を得ること;
(c)前記試料中のバイオマーカーのレベルを測定すること;ならびに
(d)前記バイオマーカーのレベルを前記バイオマーカーのベースレベルと比較すること;
を包含し、ここで前記バイオマーカーはCAPである、前記方法。 - 前記トランスジェニックマウスが、請求項1〜9または22のいずれか1項に記載のトランスジェニックマウスである、請求項31に記載の方法。
- 前記バイオマーカーのベースレベルが、(i)化合物が前記トランスジェニックマウスに投与されていない場合;(ii)前記トランスジェニックマウスに前記第1の化合物のみを投与する場合;(iii)前記トランスジェニックマウスに前記第2の化合物のみを投与する場合;(iv)対照化合物を前記トランスジェニックマウスに投与する場合;(v)前記第1の化合物と別の化合物との組み合せを前記トランスジェニックマウスに投与する場合;(vi)前記トランスジェニックマウスに前記第2の化合物と別の化合物との組み合わせを投与する場合;または(vii)2種以上の他の化合物の組み合わせを前記トランスジェニックマウスに投与する場合の前記バイオマーカーのレベルである、請求項31または32に記載の方法。
- 前記化合物が、同時または連続してのいずれかで投与される、請求項31〜33のいずれか1項に記載の方法。
- 前記化合物が免疫調節化合物である、請求項23〜34のいずれか1項に記載の方法。
- 前記免疫調節化合物が、サリドマイド、レナリドマイド及びポマリドマイドからなる群より選択される、請求項35に記載の方法。
- 前記免疫調節化合物がサリドマイドである、請求項36に記載の方法。
- 前記免疫調節化合物がレナリドマイドである、請求項36に記載の方法。
- 前記免疫調節化合物がポマリドマイドである、請求項36に記載の方法。
- 前記化合物が、パターン認識受容体(PRR)アゴニストである、請求項23〜34のいずれか1項に記載の方法。
- 前記PRRアゴニストが、TLR3アゴニスト、TLR7アゴニスト、TLR8アゴニスト、TLR9アゴニスト、RIG−1アゴニスト、MDA5アゴニスト及びAIM2アゴニストからなる群より選択される、請求項40に記載の方法。
- 前記PRRアゴニストがTLR3アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがTLR7アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがTLR8アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがTLR9アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがRIG−1アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがMDA5アゴニストである、請求項41に記載の方法。
- 前記PRRアゴニストがAIM2アゴニストである、請求項41に記載の方法。
- 前記化合物が抗体である、請求項23〜34のいずれか1項に記載の方法。
- 前記抗体が、PD−1抗体、PD−L1抗体、PD−L2抗体、CTLA−4抗体、CD38抗体、及びSLAMF7抗体からなる群より選択される、請求項49に記載の方法。
- 前記抗体がPD−1抗体である、請求項50に記載の方法。
- 前記抗体がPD−L1抗体である、請求項50に記載の方法。
- 前記抗体がPD−L2抗体である、請求項50に記載の方法。
- 前記抗体がCTLA−4抗体である、請求項50に記載の方法。
- 前記抗体がCD38抗体である、請求項50に記載の方法。
- 前記抗体がSLAMF7抗体である、請求項50に記載の方法。
- 前記抗体が、ニボルマブ(すなわち、BMS−936558、MDX−1106、ONO−4538)、MK−3475(すなわち、ペムブロリズマブ、ランブロリズマブ)、ピジリズマブ(すなわち、CT−011)、MEDI−0680(すなわち、AMP−514)、PDR−001、デュルバルマブ(すなわち、MEDI−4736)、BMS−936559(すなわち、MDX−1105)、アベルマブ(すなわち、MSB0010718C)、アテゾリズマブ(すなわち、MPDL−3280A)、イピリムマブ、ダラツムマブ、及びエロツズマブからなる群より選択される、請求項49に記載の方法。
- 前記抗体がニボルルマブである、請求項57に記載の方法。
- 前記抗体がデュルバルマブである、請求項57に記載の方法。
- 前記抗体がイピリムマブである、請求項57に記載の方法。
- 前記抗体がダラツムマブである、請求項57に記載の方法。
- 前記抗体がエロツズマブである、請求項57に記載の方法。
- 前記化合物が分子模倣物である、請求項23〜34のいずれか1項に記載の方法。
- 前記分子模倣物が、アザシチジン、ロミデプシン、ATRA、シクロホスファミド、及びセレブレックス(登録商標)からなる群より選択される、請求項63に記載の方法。
- 前記分子模倣物がアザシチジンである、請求項64に記載の方法。
- 分子模倣物がロミデプシンである、請求項64に記載の方法。
- 前記分子模倣物がATRAである、請求項64に記載の方法。
- 前記分子模倣物がシクロホスファミドである、請求項64に記載の方法。
- 前記分子模倣物がCelebrex(登録商標)である、請求項64に記載の方法。
- ステップ(a)が、前記トランスジェニックマウスに第3の化合物を投与することをさらに含む、請求項31または32に記載の方法。
- 前記第1の化合物がデキサメタゾンである、請求項31、32、または70のいずれか1項に記載の方法。
- 前記第2の化合物が、CRBN E3ユビキチンリガーゼ調節化合物(CMC)または免疫調節化合物である、請求項31、32、70、または71のいずれか1項に記載の方法。
- 前記免疫調節化合物が、サリドマイド、レナリドマイド及びポマリドマイドからなる群より選択される、請求項72に記載の方法。
- 前記第3の化合物が、イキサゾミブ、カルフィルゾミブ、エロツズマブ、ダラツムマブ、アザシチジン、ACY−241、シクロホスファミド、デュルバルマブ、アブラキサン及びニボルマブからなる群より選択される、請求項70〜73のいずれか1項に記載の方法。
- 前記化合物の組み合わせが、デキサメタゾン及びCMCを含む、請求項31または32に記載の方法。
- 前記化合物の組み合わせが、デキサメタゾン及び免疫調節化合物を含む、請求項31または32に記載の方法。
- 前記免疫調節化合物が、サリドマイド、レナリドマイド及びポマリドマイドからなる群より選択される、請求項76に記載の方法。
- 前記化合物の組み合わせが、
(a)デキサメタゾン;
(b)CMC;ならびに
(c)イキサゾミブ、カルフィルゾミブ、エロツズマブ、ダラツムマブ、アザシチジン、ACY−241、シクロホスファミド、デュルバルマブ、アブラキサン及びニボルマブからなる群より選択される化合物、を含む、請求項70に記載の方法。 - 前記化合物の組み合わせが、
(a)デキサメタゾン;
(b)免疫調節化合物;ならびに
(c)イキサゾミブ、カルフィルゾミブ、エロツズマブ、ダラツムマブ、アザシチジン、ACY−241、シクロホスファミド、デュルバルマブ、アブラキサン及びニボルマブからなる群より選択される化合物を含む、請求項70に記載の方法。 - 前記免疫調節化合物が、サリドマイド、レナリドマイド、及びポマリドマイドからなる群より選択される、請求項79に記載の方法。
- 化合物または化合物の組み合わせの効果が、抗原特異的T細胞殺傷に対する効果である、請求項28〜80のいずれか1項に記載の方法。
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