JP7191377B2 - マクロファージの分化及び免疫を改変する方法 - Google Patents
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Description
本出願は、2015年11月11日付で出願された米国仮特許出願第62/253,836号に対する優先権を主張するものであり、その内容全体が引用することにより本明細書の一部をなす。
acctggccgc catgcgcctc tcctcctccc cacctcgtgg cccgcagcag ctctccagct ttggctccgt ggactggctc tcccagagca gctgctcagg gccgacccac acccccaggc ctgccgactt ctccctgggg agcctccctg gcccaggcca gacatccggc gcccgggagc cccctcaggc cgtcagcatc aaggaggccg ccgggtcctc aaatctgcct gcgccggaga ggaccatggc cgggttgagt aaggagccaa ataccttgcg ggccccccgt gtccgcacag ccttcaccat ggagcaggtc cgcaccttgg agggcgtctt ccagcaccac cagtacctga gccctctgga gcggaagagg ctggccaggg agatgcagct ctcagaggtc cagataaaaa cctggtttca gaatcgccgc atgaaacaca aacggcaaat gcaggacccc cagctgcaca gccccttctc ggggtctctc catgcgcccc cagctttcta ctcaacgtct tctggccttg ccaatggcct gcagctgctg tgcccttggg cacccctgtc cgggccccag gctctgatgc tgccccctgg ctccttctgg ggtctctgcc aagtggcaca agaggccctg gcatctgcgg gagcttcctg ctgcgggcag cctctggcgt cccacccccc taccccaggc cggccttcgc tgggaccagc cctgtccacg gggccccggg gcctgtgtgc tatgccacag acgggggatg cattttgagg aggcacctct gactcccaca ctcgcggtct tgctgatcgc acctggctcc tacctggagg actcagttgt tctgtttaca tcctggtggc acctctcacc ctgacccaca caaaggttct ggagattact ggagaatata tataaatata tatatgtacg tatatatgta aatacacata tacgtatata taaatatata tatacatatg tgtgtgtata tatatatata tttttttttt tttttttttt tttgagacgg agtgttgctc tgtcacccag gctggagtgc aatgacgcaa tctcggctca ctgcaacctc cgcctcctgg gttcaagcga ttctccagcc tcagcctccc gagtagctgg gattacagac acccgccacc acgcccggct aattttttct atttttagta gaaatggggt ttcaccatgt tagccaggct ggtctcaaac tcctgaccct gtgatccgcc cgcctcggcc tcccaaagtg ctgggattac aggcatgagc cactgcaccc ggccctgaga atatatttat taaagccacc tcttcactga aagttaccga aagagtcggt ttaggaagga aacgaagggt cagtgaacag agtcaaatgc agaagtgggc ttgtcatggg tagggctttc ggcgtacgat aaaaggatca tttgtttttt aaaaggggtt ggaaaaactg gttttccagt tggaaacagt aaaggttgta agctttgtgt gtacaaaaga aaacagggaa tgcaggtgtg tttatagcgt tgtggttcaa gtccctctta acaagaactc caaagctgga aagcaggagg gaacaaaggt gaacatgaag gcgaggatgc tggggccctg cagtgcgctc taggctgtgc gtgagccggg actgtaccca cagcttgctg agggctgctc ttcttgggcc agggaaagca gggcagccgg gacctgcggc tgtgcctgga ctgaagctgt cccgcaggtc cccaccctcc aacacgtgct cacctgtccc cctcctcgca gcagcctcgg gacaaaacaa tgactcaagg acagcacttc tcgcagaagg tctggaagtg cccagaatgg gaggcacgga agcccctccc ggggaggact cccgcgttga tggaccgttc ttggtgcaga ctcctgactg cgtgcatgaa acctgagaca agtgcaattc cttccatgtc gccccagagt gcccaggagg caggcagtgc ggggtgccca ggcagacggg ttcagcctgc agaactggag gcgacctgtg aaacccaccc gggcacccca acaggaacag aagcgtggtc ctgcggctgc gtccccagcg agtttcactt tccccttgct cgtttctccc ttgttgtaag tgtttacaac tggcatgtgc ttttaaacgt caggtaagag gggaacagct gctgtacatc gtcctggcga gtgacaatgt gacagaagcc tgggcgaggc cctcggaggg cagcagctgg acaggggcta ctgggtttgg cctggacagc actgatttgt ggatgtggat gggggcacgt tgtccgtgat aaaagtacaa gtgcccctca caaaaaaaaa aaaaaaaa(配列番号1、下線:コーディング配列)
mrlssspprg pqqlssfgsv dwlsqsscsg pthtprpadf slgslpgpgq tsgareppqa vsikeaagss nlpapertma glskepntlr aprvrtaftm eqvrtlegvf qhhqylsple rkrlaremql sevqiktwfq nrrmkhkrqm qdpqlhspfs gslhappafy stssglangl qllcpwapls gpqalmlppg sfwglcqvaq ealasagasc cgqplashpp tpgrpslgpa lstgprglca mpqtgdaf(配列番号2、下線:ホメオドメイン)
進行した腫瘍では、TAMは腫瘍促進M2様表現型を示す。Bronte and Murray (2015), Nat Med 21, 117-119を参照されたい。TAMの可塑性は十分理解されており、様々なサイトカインがM2表現型へのTAMの極性化に関係があるとされている。Noy and Pollard (2014), Immunity 41, 49-61を参照されたい。比較すると、TAM極性化を制御する転写機構は、依然としてほとんどわかっていない。
従来の研究は、LPSによってTAMを誘導してM1表現型を示すことができることを示した。Zhang et al.を参照されたい。Hom-1がTAM可塑性に役割を果たすかどうか判断するために、本発明者らはLPSに曝露されたTAMにおけるHom-1の発現を調べた。本発明者らは、LPSで刺激された後に、TAMにおいてHom-1発現が著しく上昇されたことを見出した。Hom-1の高発現と並行し、以前の知見と一致して、TAMのLPS刺激は、炎症性サイトカイン及び細胞毒性iNOsの分泌の増加をもたらした。
Hom-1がTAMのM1極性化を促進するという本発明者らの知見は、Hom-1改変TAMが腫瘍抑制を発揮し得るかどうかを探索するよう本発明者らを促した。結腸癌から新たに単離したTAMをGPF-Hom-1又は対照GFPをコードするプラスミドでトランスフェクトした。その後、トランズウェル培養系を使用して、同じ患者の腫瘍又は正常組織と共に改変TAMを共培養した。注目すべきことに、7日間~10日間の共培養の後、GFP-Hom-1改変TAMと共にインキュベートする間、腫瘍容積は著しく減少(およそ70%)したのに対し(p<0.01)、GFPトランスフェクトTAM又はTAM単独と共にインキュベートした腫瘍においてサイズの著しい変化はなかった。腫瘍容積の縮小が、癌細胞の減少と関連したかどうか判断するため、本発明者らは組織切片作製、H&E染色、及び結腸癌細胞のCK20抗体による免疫組織化学検査を行った。本発明者らは、TAM又はGFP改変TAMと共にインキュベートした腫瘍の胞巣(nests)、コード及びシートにおいてCK20陽性腫瘍細胞が出現したことを見出した。しかしながら、CK20陽性腫瘍細胞は、GFP-Hom-1でトランスフェクトしたTAMと共にインキュベーションする間に消滅した。GFP又はGFP-Hom-1のいずれかでトランスフェクトされたTAMと共にインキュベーションする間、Hom-1改変TAMは正常な結腸粘膜の容積及び形態に対して最小の影響を及ぼしたという知見により、Hom-1改変TAMの殺腫瘍効果の特異性が実証された。
Hom-1がTAMをin vitroで殺腫瘍細胞に変換したという本発明者らの知見は、in vivoでの腫瘍形成におけるHom-1調節TAMの可能性のある役割をするよう本発明者らを促した。結腸癌をおよそ0.5cm片に切り、NSGマウスの腹側の皮下空間に外科的に播種した。1週間後、MO-Hom-1トランスフェクトTAM(Hom-1阻害)又はGFP-Hom-1トランスフェクトTAM(Hom-1発現)を、マウス尾静脈より注入した。異種移植の8週間後、MO-Hom-1トランスフェクトTAMを注入したマウスでは腫瘍が発生したが、GFP-Hom-1トランスフェクトTAMを注入したマウスでは腫瘍は発生しなかった。
TAMは、本質的に全ての腫瘍の発癌に関係するとされてきた。結腸癌細胞におけるTAMに関する研究に続いて、本発明者らは、他の種類の腫瘍まで調査を広げた。
病理検査室において、患者に由来する外科的に切除された標本から癌組織及び正常組織を得た。およそ5グラム~10グラムの組織を各腫瘤、又は腫瘤から15cm離れた正常な粘膜から収集した。また、患者の血液試料も収集した。
以前に記載された技術(Kamada N, et al, 2008; Pignata C, et al, 1990)を修正して使用し、固有層単核細胞(LPMC)を単離した。簡潔には、解剖した新鮮な粘膜及び腫瘤を、2%ウシ胎児血清(FBS)及び1mMジチオトレイトール(DTT)(Sigma- Aldrich)を含む、Ca2+フリー及びMg2+フリーのハンクス平衡塩類溶液(HBSS)(life technologies)にて10cmのペトリ皿内で濯いで、粘液を除去した。粘膜及び腫瘍をカミソリ刀によって0.5cm片に切り、1mM EDTA(Sigma-Aldrich)を含む5mLのHBSSと共に、6ウェルプレートにおいて37℃で1時間インキュベートした後、グレーメッシュ(gray-mesh)(100ミクロン)に通した。通過画分は、上皮内リンパ球及び上皮細胞を含み、フローサイトメーターによる分析であった。
その後、2%FBS、1.5mg/mLコラゲナーゼD(Roche)、0.1mg/mL Dnase Iを含むHBSS(Ca2+及びMg2+を含む)において、37℃で1時間に亘り、粘膜及び腫瘍をインキュベートした。グレーメッシュ(70ミクロン)フィルターに消化した組織を通した。通過画分を収集し、40%パーコール溶液(Pharmacia)に再懸濁した後、60%パーコール上に積層し、2000rpmにて中断せずに(without brake)30分間遠心分離を行った。界面のLPMCを収集した。製造業者の指示書に従い、CD16を枯渇させずに、EasySep(商標)ヒト単球/マクロファージ濃縮キット(StemCell Technologies)を使用して、LPMCから正常粘膜マクロファージ及びTAMを精製した。これらの技術によって単離した細胞は、ヨウ化プロピジウム(PI)染色により常に98%超が生存可能であった。腸マクロファージの純度は95%超であった。
ブリガム&ウィメンズ病院において、健康な成人ドナーに由来する末梢血単核細胞(PBMC)をフィコール密度勾配遠心分離によって単離した。製造業者の指示書に従い、CD16を枯渇させずに、EasySep(商標)ヒト単球濃縮キットを使用して、PBMCからヒト単球を精製した。精製した細胞を10ng/mLのM-CSF(PeproTech)を含む完全RPMI培地で培養した。濃縮後、単球をM-CSFを含む完全RPMI培地で5日間培養し、細胞を共培養系に使用した。
蛍光染料複合化抗体で細胞を免疫標識した後、フローサイトメトリーを使用して、TAM及び他のリンパ球の表現型の分析を行った。以下の抗体、すなわちPE複合化された抗CD3(OKT3)、抗CD25(BC96)、抗CD14(61D3)、抗CD68(eBio Y182A)、抗CD163(eBio GH161)、抗CD206、FITC複合化された抗CD4(RPA-T4)、抗CD33(HIM3-4)、APC複合化された抗CD8(OKT8)、抗CD4(OKT4)(eBioscience, Inc)を使用した。製造業者によって提供されるプロトコルに従い、PE複合化抗体を用いて、Foxp3(236A/E7)、IFN-γ、パーフォリン及びグランザイムBの細胞内の染色を行った。アイソトープ対照標識化を並行して行った。供給元により推奨される通りに抗体を希釈した。標識化細胞をCell-Questソフトウェア(BD Biosciences)を備えるFACScanフローサイトメーターで収集し、FlowJoソフトウェアによって分析した。結果を陽性細胞のパーセンテージとして表す。
トランズウェルインサート(孔径0.4μm、Costar、Corning)を12ウェルのポリスチレン組織培養プレート(ニュージャージー州フランクリンレイクスのBecton Dickinson)に入れた。粘膜及び腫瘤を計量し、抗生物質を加えた1×PBSバッファーで洗浄した後、0.5cm片に切った。およそ50mgの組織を12ウェルのトランズウェルの上部コンパートメントに蒔き、0.5mLのRPMI 1640完全培地で満たした。5×105個のTAMを50万細胞/ウェルの密度で、直接の細胞-組織の接触をせずに、下部コンパートメントに添加し、2mLのPRMI完全培地で満たした。そのプレートを37℃、5%CO2でインキュベートした。0.5mLの培養培地をサイトカイン分析のため収集し、新たな培地を3日毎に添加した。2週間の共培養の後、下部チャンバーのマクロファージを収集し、TRIzol試薬(Ambion)により全RNAを単離した。腫瘍及び正常粘膜をカリパスにより1週間に2回モニターし、(長さ×幅2)/2の式に従って、腫瘍容積を計算した。Leica EZ4D実体顕微鏡上の3メガピクセルCMOSカメラ、又はiPhone(登録商標)のデジタルカメラにより、組織の写真を撮影した。
腫瘍又は正常組織をホルマリン(ミシガン州カラマズーのFisher Scientific Company)中で固定した。CK20染色(カリフォルニア州カーピンテリアのDako、クローンKs20.8、1:50)及びヘマトキシリン/エオシン(H&E)染色を行った。オンラインでEpitope Retrieval 2を20分間使用し、またBone Polymer Refine検出キットを使用して、Leica Bone III染色プラットフォーム上でCK20染色を行った。Nikon Eclipse Ti蛍光顕微鏡により、顕微鏡分析を行った。NIS Elements画像処理ソフトウェア(Nikon)を適用するカラーカメラを使用して、40倍のオリジナル倍率で画像を取り込んだ。代表的な画像に対する明るさ及びコントラストを群間で均等に調整した。
製造業者のプロトコルに従い、リポフェクタミン2000(Life technologies)により、GFP-Hom-1の血液マクロファージ及びTAMへのトランスフェクションを行った。トランスフェクションの48時間後、細胞選別用の70μmフィルターによって細胞を濾過した。GFP陽性細胞を、無菌条件でBaker Bio-Protect Hoodのもと、BD FACSAria IIによって選別した。選別の後、細胞をRPMI 1640完全培地中で培養した。
製造業者の指示書に従い、ヒト単球Nucleofectorキット(メリーランド州ウォーカーズヴィルのLonza)を使用して、結腸TAM又はヒト初代単球を、モルフォリノ(MO)アンチセンスオリゴヌクレオチドでトランスフェクトした。簡潔には、5×106個の細胞を、2.5nmolのHom-1 MOオリゴヌクレオチド又は標準対照MOオリゴヌクレオチドのいずれかを含む100μlのnucleofector溶液に再懸濁し、Nucleofector II装置(Lonza)により電気穿孔を行った。その後、細胞を装置から直ちに出し、2mMグルタミン及び10%FBSを含む、予め温めた1mlのヒト単球Nucleofector培地と共に一晩インキュベートした。その後、細胞を完全RPMI培地に再懸濁し、適切なサイトカインで処理して、マクロファージへの分化を誘導した。いずれのMOオリゴヌクレオチドも、Gene Tools(オレゴン州フィロマス)に注文した。
eBiosciencesから得たELISAキットを使用して、E.コリ(E.coli)LPS(Sigma-Aldrich)処理した血液マクロファージ又はLPS処理したTAMの上清中のIL-1β、IL-10、TNF-α、及びIL-12p70のレベルを定量した。分析を製造業者の指示書に従って行った。
全RNAをTRIzol試薬によって単離し、RNA量をNanoDrop 2000(Thermo Scientific)によって測定した。製造業者のプロトコルに従って、SuperScript IIIファーストストランド合成システム(Life Technologies)により、等量のRNAをファーストストランドcDNA合成に使用した。従来のPCRによりHom-1 cDNAを増幅するため、本発明者らは、製造業者の指示書に従ってAccuPrime Taq DNAポリメラーゼシステム(Life Technologies)を使用した。PCR産物を2%アガロースゲル上で分離し、臭化エチジウムで染色した。GAPDHを内部対照として使用した。本発明者らは、LightCycler(480 Real-Time PCR System;Roche)上でSYBRグリーンを用いて、Hom-1及び他の遺伝子cDNAの定量的測定を行った。その後、比較Ct法(DDCT方法)を使用して、mRNAの相対的な発現プロファイルを計算した。
QuantiChromアルギナーゼアッセイキット(DARG-200;BioAssays Systems)を使用して尿素の産生を測定することにより、細胞溶解物中のアルギナーゼ活性を定量した。培養上清中の亜硝酸塩濃度を、グリース(Griess)試薬キット(Molecular Probes)を使用して特定した。
スチューデントの検定を統計分析に使用した。
本明細書に開示される全ての特徴は、あらゆる組み合わせで組み合わされてよい。本明細書に開示される各々の特徴は、同じ目的、同等の目的又は同様の目的にかなう代替となる特徴によって置き換えられてよい。このように、特に明示的に述べられない限り、開示される各々の特徴は、包括的な一連の同等の特徴又は同様の特徴のうちの単なる一例である。
Claims (16)
- 被験体の癌を治療するための医薬組成物であって、
Hom-1ポリペプチド又はHom-1ホメオボックスドメインを含むそのフラグメントをコードする外因性の核酸配列を含むように改変され、上昇したレベルのHom-1ポリペプチド又はそのフラグメントを発現し、抗腫瘍活性を示す、改変されたマクロファージ又は単球
を含む、医薬組成物。 - 前記改変されたマクロファージ又は単球が、
(1)前記癌を有する被験体に由来するマクロファージ又は単球、又は
(2)HLAが任意に一致していてもよい異種性マクロファージ又は単球
に外因性の発現コンストラクトを導入することにより生成される、請求項1に記載の医薬組成物。 - 前記外因性の核酸配列が、内因性Hom-1プロモーター又は異種性プロモーターのいずれかに作動可能に連結され、前記異種性プロモーターが任意に構成的プロモーター又は誘導性プロモーターであってもよい、請求項1又は2に記載の医薬組成物。
- 前記マクロファージがM1表現型を示すか、又は上昇したレベルのM1遺伝子、例えば、IL1β、IL6、IL12、IL23、TNFα、iNOs、CD40、CD80、CD86、CD68、TLR4、TLR2、IL-1R、MHCII、CCL15、CCL20、CXCL9、CXCL1、又はSOCS3を発現する、請求項1~3のいずれか一項に記載の医薬組成物。
- 前記被験体が、前記治療の前に、対照と比較して、前記被験体において腫瘍関連マクロファージ(TAM)におけるより低いレベルのHom-1を発現すると決定されたものである、請求項1~4のいずれか一項に記載の医薬組成物。
- 前記マクロファージが、上昇したレベルのHom-1を発現するように改変される前の、腫瘍促進マクロファージ、例えば、腫瘍関連マクロファージ(TAM)又はM2マクロファージである、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記癌が、前記癌を有する被験体の対照組織又は正常組織のマクロファージよりも低いレベルのHom-1を発現する腫瘍関連マクロファージ(TAM)に関連しており、任意に、前記癌が、癌腫、肉腫、白血病、骨肉腫、リンパ腫、黒色腫、神経膠腫、膠芽腫、褐色細胞腫、肝臓癌、卵巣癌、皮膚癌、精巣癌、胃癌、膵癌、腎臓癌、乳癌、前立腺癌、結腸直腸癌、頭頸部癌、脳腫瘍、食道癌、膀胱癌、副腎皮質癌、肺癌、気管支癌、甲状腺癌、子宮内膜癌、鼻咽腔癌、子宮頸癌、肝臓癌、転移癌、及び原発部位が未知の癌からなる群より選ばれる少なくとも一種であってもよい、請求項1~6のいずれか一項に記載の医薬組成物。
- 点滴又は注射、例えば、静脈内、髄腔内、筋肉内、腔内、気管内、腹腔内、頭蓋内、皮下、又は経皮投与を介して、前記癌を有する被験体に投与するために適している、請求項1~7のいずれか一項に記載の医薬組成物。
- 放射線、化学療法、抗体療法、又は小分子薬物療法との併用療法に使用するために適している、請求項1~8のいずれか一項に記載の医薬組成物。
- 上昇したレベルのHom-1を発現し、抗腫瘍活性を示すように遺伝子改変されたマクロファージ又は単球であって、
Hom-1ポリペプチド又はHom-1ホメオボックスドメインを含むそのフラグメントをコードする核酸配列を含むように遺伝子改変され、上昇したレベルのHom-1ポリペプチド又はそのフラグメントを発現し、抗腫瘍活性を示す、遺伝子改変されたマクロファージ又は単球。 - (1)前記癌を有する被験体に由来するマクロファージ又は単球、又は(2)前記癌を有する被験体とHLAが任意に一致していてもよい異種性マクロファージ又は単球に外因性の発現コンストラクトを導入することにより生成される、請求項10に記載のマクロファージ又は単球。
- 前記癌を有する被験体が、対照と比較して、前記被験体において腫瘍関連マクロファージ(TAM)におけるより低いレベルのHom-1を発現すると決定されたものである、請求項11に記載のマクロファージ又は単球。
- 前記癌が、前記癌を有する被験体の対照組織又は正常組織のマクロファージよりも低いレベルのHom-1を発現する腫瘍関連マクロファージ(TAM)に関連しており、任意に、前記癌が、癌腫、肉腫、白血病、骨肉腫、リンパ腫、黒色腫、神経膠腫、膠芽腫、褐色細胞腫、肝臓癌、卵巣癌、皮膚癌、精巣癌、胃癌、膵癌、腎臓癌、乳癌、前立腺癌、結腸直腸癌、頭頸部癌、脳腫瘍、食道癌、膀胱癌、副腎皮質癌、肺癌、気管支癌、甲状腺癌、子宮内膜癌、鼻咽腔癌、子宮頸癌、肝臓癌、転移癌、及び原発部位が未知の癌からなる群より選ばれる少なくとも一種であってもよい、請求項12に記載のマクロファージ又は単球。
- Hom-1ポリペプチド又はHom-1ホメオボックスドメインを含むそのフラグメントをコードする外因性の核酸配列を含み、前記核酸配列が、内因性Hom-1プロモーター又は異種性プロモーターのいずれかに作動可能に連結され、前記異種性プロモーターが任意に構成的プロモーター又は誘導性プロモーターであってもよい、請求項11~13のいずれか一項に記載のマクロファージ又は単球。
- 前記マクロファージがM1表現型を示すか、又は上昇したレベルのM1遺伝子、例えば、IL1β、IL6、IL12、IL23、TNFα、iNOs、CD40、CD80、CD86、CD68、TLR4、TLR2、IL-1R、MHCII、CCL15、CCL20、CXCL9、CXCL1、又はSOCS3を発現する、請求項11~14のいずれか一項に記載のマクロファージ又は単球。
- 前記マクロファージが、上昇したレベルのHom-1を発現するように遺伝子改変される前の、腫瘍促進マクロファージ、例えば、腫瘍関連マクロファージ(TAM)又はM2マクロファージである、請求項11~15のいずれか一項に記載のマクロファージ又は単球。
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