JP2016523930A - 骨髄異形成症候群(mds)を治療するための可溶性cd33 - Google Patents
骨髄異形成症候群(mds)を治療するための可溶性cd33 Download PDFInfo
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Abstract
Description
本出願は、2013年7月5日に出願された米国仮出願No.61/843,274、2014年1月23日に出願された米国仮出願No.61/930,798、2014年1月24日に出願された米国仮出願No.61/931,366、及び2014年4月10日に出願された米国仮出願No.61/978,009の優先権を主張し、それらは参照により完全に本明細書に組み込まれる。
本発明は、国立衛生研究所によって付与された交付金番号CA131076及び交付金番号AI056213の下で政府の支援を受けて行われた。米国政府は、本発明に対して一定の権利を有する。
eCD33−eTLR4−Fc、
eCD33−eRAGE−Fc、
eTLR4−eRAGE−Fc、
eRAGE−eTLR4−Fc、
eCD33−eTLR4−eRAGE−Fc、
eCD33−eRAGE−eTLR4−Fc、
eTLR4−eCD33−eRAGE−Fc、
eRAGE−eCD33−eTLR4−Fc、
eTLR4−eRAGE−eCD33−Fc、及び
eRAGE−eTLR4−eCD33−Fc
から成る群より選択される式を含み、
式中、「eCD33」はヒトCD33の細胞外ドメインであり、
式中、「eTLR4」はTLR4の細胞外ドメインであり、
式中、「eRAGE」はRAGEの細胞外ドメインであり、
式中、「Fc」は免疫グロブリンFc領域であり、そして、
式中、「−」はペプチドリンカーまたはペプチド結合である。
eCD33−Fc−Avi、
eTLR4−Fc−Avi、
eRAGE−Fc−Avi、
eCD33−eTLR4−Fc−Avi、
eCD33−eRAGE−Fc−Avi、
eTLR4−eRAGE−Fc−Avi、
eRAGE−eTLR4−Fc−Avi、
eCD33−eTLR4−eRAGE−Fc−Avi、
eCD33−eRAGE−eTLR4−Fc−Avi、
eTLR4−eCD33−eRAGE−Fc−Avi、
eRAGE−eCD33−eTLR4−Fc−Avi、
eTLR4−eRAGE−eCD33−Fc−Avi、及び
eRAGE−eTLR4−eCD33−Fc−Avi
から成る群より選択される式を含み、
式中、「eCD33」はヒトCD33の細胞外ドメインであり、
式中、「eTLR4」はTLR4の細胞外ドメインであり、
式中、「eRAGE」はRAGEの細胞外ドメインであり、
式中、「Fc」は免疫グロブリンFc領域であり、そして、
式中、「Avi」は、ビオチン及びATPの存在下で、ビオチンリガーゼ(BirA)によってビオチン化され得る任意のビオチン受容体ペプチドであり、
式中、「−」はペプチドリンカーまたはペプチド結合である。
担腫瘍マウス及び癌患者で蓄積することが知られている未成熟の骨髄由来サプレッサー細胞(MDSC)は、癌の進行の原因となる部位特異的炎症性のT細胞免疫抑制エフェクター細胞である(Gabrilovich,D.I.,et al.2009.Nat Rev Immunol 9:162−174;Kusmartsev,S.,et al.2006.Cancer Immunol Immunother 55:237−245)。それらの抑制活性は、炎症関連のシグナル伝達分子によって、例えば危険関連分子パターン(DAMP)ヘテロダイマーS100A8/S100A9(それぞれ骨髄関連タンパク質(MRP)−8及びMRP−14としても知られている)によって、TLR4のライゲーションを介して部分的に駆動される(Ehrchen,J.M.,et al.2009.J Leukoc Biol 86:557−566;Vogl,T.,et al.2007.Nat Med 13:1042−1049)。しかしながら、ネズミCD11b+Gr1+ MDSCは、大多数のメカニズム研究の基礎を形成するが、それらのヒトでの対応物に関する報告はずっと少なかった。ヒトMDSCは、成熟免疫細胞のマーカーを殆ど欠いている(LIN−、HLA−DR−)が、CD33、すなわちレクチン(Siglec)のシアル酸結合免疫グロブリン様(Ig)スーパーファミリーのプロトタイプメンバーを有する(Gabrilovich,D.I.,et al.2009.Nat Rev Immunol 9:162−174;Talmadge,J.E.2007.Clin Cancer Res 13:5243−5248;Talmadge,J.E.,et al.2007.Cancer Metastasis Rev 26:373−400;Crocker,P.R.,et al.2007.Nat Rev Immunol 7:255−266)。重要なことには、CD33は、その正確な作用は知られていないが、免疫抑制と関連がある免疫受容体チロシン系抑制モチーフ(ITIM)を有する(Crocker,P.R.,et al.2007.Nat Rev Immunol 7:255−266)。
いくつかの実施形態では、CD33/S100A9阻害剤は、内因性S100A9と結合して隔離し、そしてMDSC上のCD33受容体に対するその結合を阻害する。したがって、いくつかの実施形態では、CD33/S100A9アンタゴニストは、S100A9結合ドメインを含有する分子である。他の実施形態では、CD33/S100A9阻害剤は、MDSC上の内因性CD33受容体と結合して阻害する。したがって、いくつかの実施形態では、CD33/S100A9アンタゴニストは、CD33結合ドメインを含有する分子である。
例えば、CD33/S100A9阻害剤は、可溶性CD33受容体であり得る。「可溶性受容体」は、細胞膜に結合されない受容体ポリペプチドである。可溶性受容体は、最も一般的には、膜貫通型ドメイン及び細胞質ドメインを欠くリガンド結合性受容体ポリペプチドである。可溶性受容体は、追加のアミノ酸残基、例えば、ポリペプチドの精製を提供するか、またはポリペプチドの基質への結合のための部位を提供するアフィニティータグを含むことができる。多くの細胞表面受容体は、タンパク質分解によって生成される天然の可溶性対応物を有する。可溶性受容体ポリペプチドは、膜固定またはシグナル変換を提供するのに十分なこれらのセグメント部分を欠く場合、それぞれ、実質的に膜貫通型及び細胞内ポリペプチドセグメントを含有しないと言われる。
18−DPN FWLQVQESVT VQEGLCVLVP CTFFHPIPYY DKNSPVHGYW FREGAIISRD SPVATNKLDQ EVQEETQGRF RLLGDPSRNN CSLSIVDARR RDNGSYFFRM ERGSTKYSYK SPQLSVHVTD LTHRPKILIP GTLEPGHSKN LTCSVSWACE QGTPPIFSWL SAAPTSLGPR TTHSSVLIIT PRPQDHGTNL TCQVKFAGAG VTTERTIQLN VTYVPQNPTT GIFPGDGSGK QETRAGVVH−259(配列番号1)、
またはそのフラグメントもしくは変異体を有することができ、例えば、配列番号1と少なくとも65%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%の配列同一性を有することができ、ここで、そのフラグメントもしくは変異体はS100A9と結合することができる。
したがって、ヒトCD33の細胞外ドメインは、これらSNPの任意の1つ以上と共に配列番号1のアミノ酸配列を有することができる。
例えば、ヒトCD33の細胞外ドメインは、以下のアミノ酸配列:
18−DPN FX1LQVQESVT VQEGLCVLVP CTFFHPIPYY DKNSPVHGYW FREGAIISX2D SPVATNKLDQ EVQEETQGRF RLLGDPSRNN CSLSIVDARR RDNGSYFFRM ERGSTKYX3YK SPQLSVHVTD LTHRPKILIP GTLEPGHSKN LTCSVSWACE QGTPPIFSWL SAAPTSLGPR TTHSSVLIIT PRPQDHGTNL TCQVKFAGAG VTTERTIQLN VTYVPQNPTT GIFPGDGSGK QETRAGVVH−259
も有することができる、ここで、X1はWまたはR;X2はRまたはG;そしてX3はSまたはNである(配列番号2)。
19−PN FWLQVQESVT VQEGLCVLVP CTFFHPIPYY DKNSPVHGYW FREGAIISRD SPVATNKLDQ EVQEETQGRF RLLGDPSRNN CSLSIVDARR RDNGSYFFRM ERGSTKYSYK SPQLSVHVTD−135(配列番号3)、
またはそのフラグメントもしくは変異体を有し、例えば、配列番号3と少なくとも65%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%の配列同一性を有し、ここで、そのフラグメントもしくは変異体はS100A9と結合することができる。vCD33は、開示されるSNP(すなわちW22R、R69G、S128N)の任意の1つ以上を有することもできる。したがって、いくつかの実施形態では、vCD33部分は、以下のアミノ酸配列:
19−PN FX1LQVQESVT VQEGLCVLVP CTFFHPIPYY DKNSPVHGYW FREGAIISX2D SPVATNKLDQ EVQEETQGRF RLLGDPSRNN CSLSIVDARR RDNGSYFFRM ERGSTKYX3YK SPQLSVHVTD−135
を有し、ここでX1はWまたはR;X2はRまたはG;そしてX3はSまたはNである(配列番号4)。
24−ESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL LVEVERMECA TPSDKQGMPV LSLNITCQMN K−631 (配列番号5)、
またはそのフラグメントもしくは変異体を有することができ、例えば、配列番号5と少なくとも65%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%の配列同一性を有するアミノ酸配列を有することができ、ここでそのフラグメントもしくは変異体はS100A9と結合することができる。
23−AQNITARI GEPLVLKCKG APKKPPQRLE WKLNTGRTEA WKVLSPQGGG PWDSVARVLP NGSLFLPAVG IQDEGIFRCQ AMNRNGKETK SNYRVRVYQI PGKPEIVDSA SELTAGVPNK VGTCVSEGSY PAGTLSWHLD GKPLVPNEKG VSVKEQTRRH PETGLFTLQS ELMVTPARGG DPRPTFSCSF SPGLPRHRAL RTAPIQPRVW EPVPLEEVQL VVEPEGGAVA PGGTVTLTCE VPAQPSPQIH WMKDGVPLPL PPSPVLILPE IGPQDQGTYS CVATHSSHGP QESRAVSISI IEPGEEGPTA GSVGGSGLGT LA−342 (配列番号6)、またはそのフラグメントもしくは変異体を有することができ、例えば、配列番号6と少なくとも65%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%の配列同一性を有するアミノ酸配列を有することができ、ここで、そのフラグメントもしくは変異体はS100A9と結合することができる。
開示される組成物及び方法で使用できる抗体としては、任意のクラスの全免疫グロブリン(すなわち、完全な抗体)、そのフラグメント、及び少なくとも抗体の抗原結合可変ドメインを含有する合成タンパク質が挙げられる。可変ドメインは、抗体間で配列が異なり、その特定の抗原のためのそれぞれの特有な抗体の結合及び特異性で使用される。しかしながら、可変性は、通常は、抗体の可変ドメイン全体に均一に分布されない。可変性は、典型的には、軽鎖及び重鎖の可変ドメインの両方にある相補性決定領域(CDR)または超可変領域と呼ばれる3つのセグメントに集中している。可変ドメインのより高度に保存される部分は、フレームワーク(FR)と呼ばれる。天然の重鎖及び軽鎖の可変ドメインは、それぞれ、3つのCDRによって結合された主にβシート配置をとる4つのFR領域を含み、これらのCDRは、ループを形成して、βシート構造と結合し、場合によっては、その一部を形成する。各鎖中のCDRは、他の鎖からのCDRと共にFR領域によって極めて接近して一体的に保持されており、抗体の抗原結合部位の形成に寄与する。
「アプタマー」という用語は、特定の標的分子に結合するオリゴ核酸またはペプチド分子を指す。これらの分子は、一般的に、ランダム配列プールから選択される。選択されたアプタマーは、固有の3次構造に適応し、そして高い親和性及び特異性で標的分子を認識することができる。「核酸アプタマー」は、そのコンホメーションを介して標的分子に結合し、それにより標的分子の機能を阻害または抑制するDNAまたはRNAオリゴ核酸である。核酸アプタマーは、DNA、RNA、またはその組み合わせによって構成され得る。「ペプチドアプタマー」は、足場タンパク質内に挿入された可変ペプチド配列を有するコンビナトリアルタンパク質分子である。ペプチドアプタマーの同定は、典型的には、厳密な酵母ジハイブリッド条件下で行われ、そしてそれは、選択されたペプチドアプタマーが安定的に発現され、そして正確に細胞内環境で折り畳まれる確率を高める。
開示される組成物は、薬学的に許容される担体と組み合わせて治療に使用することができる。「薬学的に許容される」とは、物質が生物学的にまたはそれ以外においても不適切ではない、すなわち、その物質が、望ましくない生物学的効果を生じることなく、またはそれを含有する医薬組成物の他の成分のいずれかと有害な相互作用を起こすことなく、核酸またはベクターと一緒に、対象に投与可能であることを意味している。担体は、当業者には公知であるように、当然に、活性成分の分解を最小化するとともに、対象における副作用を最小化するように選択される。
また、本明細書で開示されるCD33/S100A9アンタゴニストを含む組成物を対象に投与することを含む、S100A9活性によって引き起こされるかまたは悪化する、対象における疾患または状態を治療する方法も開示する。
開示されるCD33/S100A9阻害剤は、S100A9活性によって引き起こされるかまたは悪化する疾患を治療するために対象に治療的に有効な量を投与することができる。開示される、医薬組成物を含む組成物は、局所または全身の治療が望ましいか否かによっていくつかの方法で、治療領域に投与することができる。例えば、開示される組成物は、静脈内に、腹腔内に、筋肉内に、皮下に、腔内に、または経皮的に投与することができる。組成物は、経口的に、非経口的に(例えば、静脈内に)、筋肉内注射によって、腹腔内注射によって、経皮的に、体外的に、眼科的に、経膣的に、直腸に、鼻腔内に、局所的になどで投与することができ、例えば局所鼻腔内への投与または吸入剤によって投与してもよい。
対象のMDSを治療するのに用いることができる薬剤を同定する方法も、本明細書で提供する。本方法は、CD33とS100A9が結合する条件下でCD33及びS100A9を含む試料を提供すること、その試料を候補薬剤と接触させること、CD33/S100A9結合のレベルを検出すること、そしてその結合レベルを対照と比較することを含むことができ、ここで、対照と比較されたCD33/S100A9結合の減少によって、炎症性疾患を治療するために使用できる薬剤を同定する。
「抗体」という用語は標的抗原と選択的に結合する天然または合成抗体を指す。この用語はポリクローナル及びモノクローナル抗体を包含する。完全な免疫グロブリン分子に加えて、「抗体」という用語には、それらの免疫グロブリン分子のフラグメントまたはポリマー、及び標的抗原と選択的に結合する免疫グロブリン分子のヒトまたはヒト化版も含まれる。
方法
MDS患者
MDSの患者の大多数は、特に明記しない限り低リスクであった。すべての患者を、中央精査によって確認し、世界保健機関基準または国際予後判定システム(IPSS)にしたがって分類した。患者は、H.Lee Moffitt Cancer Center & Research InstituteのMalignant Hematology clinic及びオランダにあるRadboud University Nijmegen Medical Centre,Department of Hematologyから募集採用した。前記のように、フィコール・ハイパック比重遠心によって、骨髄単核球(BM−MNC)を、ヘパリン化BM吸引液から単離した(Wei,S.,et al.2009.Proc Natl Acad Sci U S A 106:12974−12979)。系統(Lin−)マーカー(CD3、CD14、CD16、CD19、CD20、CD56)及びHLA−DRの発現を欠くCD33+細胞の蛍光標識細胞分取(FACS)によってMDSCを同定し精製した。
すべてのマウスの作業は、南フロリダ大学の動物実験委員会の承認を得た。野生型(WT)FVB/NJマウスはジャクソン研究所から購入し、S100A9ノックアウトマウス(KO)及びS100A9トランスジェニックマウス(Tg)を既にされているように作製し、使用した(Cheng,P.,et al.2008.J Exp Med 205:2235−2249;Manitz,M.P.,et al.2003.Mol Cell Biol 23:1034−1043)。S100A9TgマウスはFVB/NJホモ接合マウスから作製し、15世代を超えて飼育した。競合移植実験のために、18週齢のFVB/NJ野生型雌のマウスを、回転ガンマ線照射装置(rotating gamma irradiator)で総線量900Gyを1回で照射した。同時に、製造者のプロトコルに従って磁性細胞分取(MACS、Millitenyi Biotech)によってHSCが富化された、同一年齢層の雄WTまたはS100A9Tgマウス脛骨及び大腿骨からBM細胞を単離した。6時間照射後に1x107富化HSCを、レシピエントマウスへ尾静脈注射によって投与した。次いで、マウスを、無菌箱下での体重測定のために一日おきにモニターした。CBCのための末梢血は、毎週センターで動物飼養場のスタッフによって前眼窩の静脈(antero−orbital vein)から採取した。8週までに(WTレシピエントに移植した後、3x103細胞/血液1ml超のWBC)マウスをCO2呼吸によって安楽死させ、その時点で心臓穿刺し、続いて脛骨及び大腿骨(既に記載した)及び脾臓を切開することによって末梢血を採取した。
FISHはCytogenetics Laboratory of Moffitt Cancer Centerで行った。その詳細な方法は既に記載されている(Wei,S.,et al.2009.Proc Natl Acad Sci U S A 106:12974−12979)。MDSC陽性(MDS−MDSC)細胞由来及びMDSC陰性細胞由来の標的DNAを、市販の検査(Abbott laboratory)を使用してdel5qまたはdel7qを有することが予め確認された同じ患者から精製した。
BM−MNCをMDS患者から精製し、3x105細胞/mlの濃度に希釈し、顕微鏡スライド上にサイトスピンし、そしてメタノール/アセトン(割合3:1、−20℃で30分間)で固定した。血清との非特異的結合をブロックする前に、トリトンX−100バッファーで5分間及び50mMのトリスバッファー(pH7.4)で10分間洗浄を行った。そのスライドを、一次抗体:すなわちウサギ抗CD33抗体(1:100希釈、Santa Cruz)、マウス抗グランザイムB(1:100希釈、Fitzgerald Industries)及びマウス抗ヒトCD71(1:100希釈、BD Biosciences)で染色し、続いて、それらの各二次抗体、すなわちAlexaFluor−594ヤギ抗ウサギIgG(Invitrogen)、FITCヤギ抗マウス(Sigma)及びAlexa−350ヤギ抗マウスIgG(Molecular Probes)で染色した。試料(1:50希釈、Abd Serotec)に添加する前に、Molecular Probesのキットを用いて、ラット抗ヒトグリコフォリンAを、Alexa−647にプレコンジュゲートさせ、続いてそのスライドを水性培地(Molecular Probes,US)と一緒にマウントした。免疫蛍光を、Zeiss製自動化直立型蛍光顕微鏡と、キャプチャープログラムAxioVisionを有するNikon製カメラでキャプチャーされたイメージとを使用して、検出した。S100A9がトランスフェクトされたSJCRH30細胞の免疫染色のための詳細な方法は、既に出版されている(Chen,X.,et al.2008.Blood 113(14):3226−34)。詳しくは、CD33及びS100A9の検出可能な発現レベルを欠くSJCRH30細胞を、48〜72時間、S100A9またはS100A8(陰性対照)でトランスフェクトした。CD33融合体との培養後(2μg/ml)、1×104個の細胞を、スライドの上にサイトスピンし、次いで、二次抗ヒトIgG1−APCで染色した後免疫蛍光顕微鏡検査によって分析した。同様に、CD33で安定にトランスフェクトされたSJCRH30細胞を、様々な時点間でDDKでタグ付けされたrhS100A9と培養した。
MDSCがT細胞抑制を媒介できるか否かを測定するために、FACSによって、CD45+ CD33+ CD11b+ Lin−細胞を、MDS患者の完全骨髄から分取した。次の抗原:すなわち、CD45−PECy7、CD33−PECy5、CD11b−FITC、CD3−PE、CD14−PE、CD20−PE(すべてBeckman Coulter,Fullerton,CA,USA)、CD16−PE、CD19−PE(DAKO,Glostrup,Denmark)及びCD56−PE(BD Biosciences,San Diego,CA,USA)を使用した。T細胞は、自己末梢血から、CD3マイクロビーズ(Miltenyi Biotec、Aubern、CA、USA)を使用して磁性活性化細胞分取(MACS)によって分離した。20,000個のT細胞を、10%ヒト血清PAA(PAA Laboratories,Pasching,Austria)を補ったIscoveの修飾ダルベッコ培地(IMDM;Invitrogen,Carlsbad,CA)を96ウェル丸底プレートに3連で播種した。培養物を、30U/mlのIL−2(Chiron,Emeryville,CA,USA)及びT細胞のビーズに対する割合が1:2の抗CD3/抗CD28コーテッドビーズ(Invitrogen,Carlsbad,CA,USA)で刺激した。MDSCを1:2及び1:4の割合でT細胞培養物と混合し、10ng/mlのGM−CSFを補ってMDSCの生育力をサポートした。共培養3日後、培養上清を採取して、ELISA(Pierce Endogen,Rockford,IL,USA)によってIFN−γ濃度を測定した。その後、0.5μCiの3H−チミジン(Perkin Elmer,Groningen,the Netherlands)を各ウェルに加え、一晩培養した後、1205 Wallac Betaplateカウンターを使用して3H−チミジンの取り込みを測定した。増殖とIFN−γ生成の違いが統計的に有意であったか否かを測定するために、一元配置分散分析を、Bonferronの事後検定とともに使用した。統計的有意性をp値<0.05で認めた。
ヒトBMから、またはS100A9Tg、S100A9KOもしくはWTの脛骨と大腿骨から単離された細胞を、室温で5分間ACK (Sigma)に供して赤血球を溶解した。次いで、残留しているBM細胞を、完全なメチルセルロース培地(メトカルト完全培地)中に必要なサイトカイン及び成長因子(StemCell Technologies)と一緒に播種し、その混合物を、グリッドされた35mm培養皿(2×105細胞/皿)に2連で入れ、7〜14日間、5%のCO2中で37℃に培養した。培養後、BFU−E及びCFU−GMのコロニーを、手動で特定し、倒立光学顕微鏡を使用して計数した。ATRAで処置したマウスを使用して行ったコロニー形成能アッセイでは、250μg(200μl)のATRAまたはビヒクル(オリーブ油)を5日連続経口投与してから2日間安静にさせた。
RT−PCR及び定量的RT−PCR(qRT−PCR)反応を、iQ SYBR Green Supermix(BioRad)によって行った。反応混合物(総量25μl)は、12.5μlのiQ SYBR green supermix、0.25μlのフォワードプライマー(s GAPDH)(20μM)、11μlのRNaseを含まない水、及び1.0μlのcDNAを含有していた。次のサイクルを行った。すなわち、95℃で3分を1回、40の増幅サイクル(95°Cで15秒、56°Cで60秒)、95℃で1分を1回、cDNAテンプレートを用いない1つの陰性対照1回をアッセイ毎に実施した。dsDNA Iの最適融点及び最低55℃及び融解曲線(80x10秒 55℃、10秒当たり0.5℃増加)。反応の効率は、前もって最適化した。各個体当たりの転写コピー数を、GAPDH発現に正規化することによって計算した。各患者に関する遺伝子発現の相対レベルを、5つの対照で観察された平均発現レベルに正規化することによって計算した。CD33をトランスフェクトしたSJCRH 30細胞及びトランスフェクトしていないSJCRH 30細胞を、1μgのrhS100A9で20分間処理し、そしてその発現を、全RNA由来のIL10及びTGFβの存在に関してQ−PCRによって測定し、そしてΔΔCt法で計算した。そこで、rhS100A9未処理の細胞は実験上の対照であり、ハウスキーピング遺伝子GAPDHは内部標準であった。エラーバーは3つの別の実験の標準誤差を表している。
CD33/Siglec 3外部ドメインの組換え可溶性融合体を、既に記載のように構成した(Cannon,J.P.,et al.2012.Immunogenetics 64:39−47;Cannon,J.P.,et al.2011.Methods Mol Biol 748:51−67;Cannon,J.P.,et al.2008.Immunity 29:228−237)。具体的には、CD33/Siglec 3外部ドメインをコードするcDNAフラグメントを、PCRによって増幅し、ヒトFcγをコードし、続いてE.coliビオチンリガーゼのためのc−末端認識部位をコードするベクター中に挿入した。このベクターは、細胞外Ig型ドメインをコードする遺伝子セグメントの、ヒトIgG1のFc領域への融合を促進するために操作されている。その組換えタンパク質は、リポフェクタミン(Invitrogen)を使用して、トランスフェクション後に293T細胞で発現され、25mlのOPTI−MEM I 無血清培地を3連続回収した。回収物を、プールし、500gで10分間遠心分離して砕片を除去し、0.02%のアジ化ナトリウム中に4℃で保管した。培養上清中のCD33融合体の濃度は、ブラッドフォードアッセイ(Biorad,Carlsbad,CA)によって測定した。
ゲル内トリプシン消化後、ペプチドを真空遠心下で抽出し濃縮した。エレクトロスプレーイオントラップ質量分析計(LTQ,Thermo,San Jose,CA)に連結されたナノフロー液体クロマトグラフ(Easy−nLC,Proxeon,Odense,Denmark)を、タンデム型質量分析ペプチド塩基配列決定実験のために使用した。試料を、まず最初に、トラップカラム(BioSphere C18逆相樹脂,5μm,120Å,100μm ID,NanoSeparations,Nieuwkoop,Netherlands)に充填し、8ml/分で3分間洗浄した。そのトラップされたペプチドを、分析カラム(BioSphere C18 逆相樹脂,150mm,5μm,120Å,100μm ID,NanoSeparations,Nieuwkoop,Netherlands)上へ溶離した。ペプチドを、300nl/分の流速で、5%Bから45%B(溶媒A:2%のアセトニトリル+0.1%のギ酸;溶媒B:90%のアセトニトリル+0.1%のギ酸)の勾配で60分間溶離した。5つのタンデム質量スペクトルを各サーベイスキャン後にデータ依存的な方法で集めた。配列を、ヒトIPIエントリーに対するMascot(www.matrixscience.com)検索を使用して割り当てた。システインのカルバミドメチル化、メチオニン酸化、及びアスパラギンとグルタミンのアミド分解を様々な修飾として選択し、2までのトリプシン消化切断ミス(missed tryptic cleavage)が許容された。前駆体質量許容値(mass tolerance)は2.5に設定し、フラグメントイオン許容値は0.8に設定する。Mascotの結果をScaffoldで編集し、それを、ペプチドの割り当て及びタンパク質同定の手動検査に使用した。
S100A9がトランスフェクトされたSJCRH 30細胞のCD33−融合結合細胞溶解物に関するELISAアッセイ。製造者の提案に従って、96ウェル平底ELISAプレートを、1μg/mlのモノクローナル抗S100A9lで一晩コートした。PBS−Tで1回洗浄した後、トランスフェクトされていない細胞(陰性)またはS100A9でトランスフェクトされた細胞由来の50μlの溶解物をウェルに加えた。440nmでのELISA HRP反応分析にしたがって示されているように、二次抗体は、S100A9ポリクローナル抗体(陽性対照)またはCD33融合体であった。
CD33プラスミド(GeneCopeia)を、pShuttle−IRES−hrGFP−1ベクター(CMVプロモーター及びhrGFPを含有)中にサブクローニングした。次いで、PmeIで消化されたシャトルベクターを、pAdEasy−1(ウイルスバックボーンを含有)を有するエレクトロコンピテントBJ5183細菌に形質転換し、カナマイシンLBプレート上で選択した。細菌中のプラスミドを、plasmid maxiprep system(Qiagen)を使用して増幅し精製した。完全なアデノウイルスベクターを、PacI消化によって線形化し、次いでリポフェクタミン(Invitrogen)を使用してAD293細胞内にトランスフェクトした。すべての組換えアデノウイルスをAD293細胞中で増幅した。ウイルスストックは、AD293細胞を増幅し、続いて、標準的な2ステップのCsCl勾配超遠心分離、透析、そして−80℃でグリセロールストック(10%v/v)中に保管することによって、得た。各ウイルスストックの力価は、AD293細胞を使用してプラーク形成アッセイによってルーチン的に検査し1011〜1012pfuであった。
ヒトS100A8、S100A9及びCD33及び陰性対照(標的無し)のためのSureSilencing(商標)shRNAプラスミドをSABiosciencesから購入した。293Tの細胞を、製造者の取扱い説明書にしたがい、トランスフェクション試薬(SABiosciences)を使用して、トランスフェクトした。6時間の培養後、トランスフェクション試薬を除去し、10%のウシ胎児血清で補充された新鮮なDMEMで置換した。ウイルス含有培地を24〜48時間後に集めた。プラスミド、pcDNA3野生型DAP12及びP23−DAP12を、HindIII及びXhoI(Promega)で切断し、そしてDNAポリメラーゼI Large(KlenowI)(New England Biolabs Inc.)を使用して陥凹3′末端を満たした。GFP発現カセット(Addgene Organization)を含有するpWPIを、PMEI(New England Biolabs Inc.)を使用して消化した。DNA及びベクターを切断した後、Strata Prep PCR精製キット(Qiagen)によってpWPIを精製し、DNAをベクターpWPI中に結紮し(Takara DNAライゲーションキット,Fisher)、そしてSTBL2コンピテント細胞を形質転換させた(Invitrogen)。293T細胞を、標準プロトコルにしたがって4:3:1の比率でLipofectemine−2000(Invitrogen)を使用して、pWPIレンチウイルスベクター、そのパッケージングプラスミド、psPAX2、及びエンベローププラスミド、pMD2.G(Addgene Organization)で、トランスフェクトした。6時間の培養後、トランスフェクション試薬を除去し、10%のウシ胎児血清で補充された新鮮なDMEMで置換した。ウイルス含有培地を24〜48時間後に集めた。細胞感染を上記のように実行した。第1感染の4日後に、形質導入された細胞を、99%超の純度でGFP+細胞を分取するFACSによって単離した。
MDS患者から単離されたMDSCを、8μg/mlのポリブレン(polyberene)の存在下で、24時間間隔でウイルス含有感染培地を用いて3回感染させた。各感染のために、1ウェル当たり1×106個の細胞を12ウェル皿で平板培養した。第1感染の4日後に、細胞を回収し、リアルタイムPCR、ウェスタンブロット解析、フローサイトメトリー、またはコロニー形成能アッセイのために使用した。
BM−MNCを、2%のBSAバッファーを有するPBS中適切な特異的コンジュゲート化抗体で染色した。MDSC分取のために、陽性対照としてFITC抗CD3及びFITC抗HLA−DRと、陰性対照としてアイソタイプIgGを使用して、非特異的染色を検出した。細胞を穏やかに混合し、暗所で4℃において30分間培養した。試料をPBSで洗浄し、500gで5分間遠心分離した。表現型分析のみで使用した細胞に関しては、PBS中0.5mlの1%パラホルムアルデヒドを分析前に加えた。
アルギナーゼ活性を、以前に記載された通り、細胞溶解物で測定した(Youn,J.I.,et al.2008.J Immunol 181:5791−5802)。簡潔に言えば、細胞を100μlの0.1%Triton X−100で30分間溶解した。続いて、100μlの25mMのTris−HCl及び10μlの10mMのMnCl2を加え、そして酵素を56℃で10分間加熱することによって活性化させた。アルギニン加水分解を、120分間、37℃で、100μlの0.5MのL−アルギニン(pH9.7)と一緒にその溶解物を培養することによって実行した。その反応は、900μlのH2SO4(96%)/H3PO4(85%)/H2O(1/3/7(v/v/v))で停止させた。尿素濃度を、40μlのα−イソニトロソプロピオフェノン(100%エタノール中に溶かした)を加え、続いて30分間95℃で加熱した後で、540nmで測定した。
等しい体積の培養上清(100μl)を、再蒸留水中のGreiss試薬液(5%リン酸中1%スルファニルアミド及び0.1%N−1−ナフチルエチレンジアミン二塩酸塩)と混合し、そして室温で10分間培養した。その混合物の吸光度を、マイクロプレートプレートリーダー(Bio−Rad)を使用して550nmで測定した。亜硝酸塩濃度を、試験試料に関する吸光度値を0.25mMの亜硝酸ナトリウムの系列希釈によって作製された標準曲線と比較することによって、測定した。
1%のNP−40、10mMのTris、140mMのNaCl、0.1mMのPMSF、10mMのヨードアセトアミド、50mMのNaF、1mMのEDTA、0.4mMのオルトバナジン酸ナトリウム、10μg/mlのロイペプチン、10μg/mlのペプサチン、及び10μg/mlのアプロチニン中に細胞ペレットを再懸濁し、そして30分間氷上で溶解することによって、細胞溶解物を調製した。細胞溶解物を12,000gで15分間遠心分離して核及び細胞片を除去した。可溶性抽出物のタンパク質濃度をBioRad(Bradford)タンパク質アッセイを使用することによって測定した。50μgのタンパク質(1レーン当たり)を、電気泳動によって10%のSDS−ポリアクリルアミドゲル上で分離し、次いでPVDF膜へと移した。次に示す抗体:すなわち、抗S100A8または抗S100A9(それぞれMRP8またはカルグラヌリンA及び抗MRP14またはカルグラヌリンB、Santa Cruz);抗S100A8/A9(Santa Cruz);抗ホスホErk、抗全Erk、抗ホスホSyk、及び抗全Syk(Cell Signaling)に関して膜をプローブした。タンパク質を、増強化学発光検出システム(ECL,Amersham)で検出した。S100A9でトランスフェクトされていない、空のベクター及びS100A9でトランスフェクトされたSJCRH30またはAD293細胞由来の溶解物を、第1溶解物(50μgで開始)で連続的に希釈し(図に示したように)、続いてニトロセルロース膜上に充填し、そして5%のミルクで40℃で一晩ブロックした。室温の2時間のCD33融合体と一緒に培養し、そして抗ヒトIgG HRPコンジュゲート化二次抗体で染色した後、その膜を、洗浄し、そしてX線写真分析に使用して、CD33に対する特異的なS100A9の結合を証明した。その後で、その膜は、ニトロセルロース膜における各ドット上に比較的等しい充填量のタンパク質を示すためのクマシーブルー染色のために用いた。
CBCを、Moffitt Cancer Centerの動物飼養場においてanimal core laboratoryの病理学職員によって実行した。Heska Hematrue血液分析装置で表1に記載したようにマウスの血液パラメーターを測定した。
骨髄細胞を、以前に記載されているように(Xu,S.,et al. 2010. J Biomed Biotechnol 2010:105940)、6月齢のS100A9Tgマウス及びwt対照マウス由来の左右の脛骨と大腿骨から得た。ネズミ脾細胞のタッチプリント(touch prit)を、記載されたように調製した(Ioachim,H.L.,et al.2008.Iochim’s lymph node pathology.Chapter 3.cytopathology.Wolters Kluwer/Lippincott Williams &Wilkins.:p21−22)。骨髄穿刺液及びタッチインプリント(touch−imprint)をライトギムザ染色を使用して染色した。骨髄の部分及び脾臓の切片を、10%リン酸緩衝の中性ホルマリン中に固定し、脱石灰し(骨髄に適用されるのみ)、そしてルーチンの手順によってパラフィン中に包埋した。切片を4μmで切断し、ヘマトキシリン−エオジン(H&E)及び過ヨウ素酸シッフ反応(PAS)で染色した。MDSの骨髄異形成の特徴特性の存在を、経験豊かな血液病理学者が評価した。BMコア生検は、成熟三血球系造血(maturing trilineage hematopoiesis)で50%の細胞充実性を示している(H&E、200x)。図5Eは、正常な分葉を有し正常な外観を呈する巨核球を示すBM生検の高倍率ビューを示す。混合された骨髄前駆体及び赤芽球前駆体は、M:E比が約2:1で正常に分布している(H&E,600x)。ライトギムザ染色されたBM穿刺液は、形成異常の特徴が無い全三血球系における完全な成熟を示す(ライトギムザ、1000x)。インレットには正常な分葉のある巨核球が示されている(図5F)。マウス脾臓のタッチインプリントは、所々で赤血球生成前駆体と混ざり合った小さく且つ成熟した外観のリンパ球の優勢を示す(ライトギムザ、1000x)(図5G)。BMコア生検では、特に小さい形態の巨核球増加による約95%の細胞過形成がみられる(H&E,200x)(図5H)。高倍率により、単一もしくは低分葉の、またはばらばらの核及び数の著しい増加による形成異常巨核球が強調されている(H&E,600x)(insert)(図5I)。インレットには、低分葉(hypolobation)の2つの著しい形成異常の小さな巨核球(micromegakaryocyte)が含まれている。BM穿刺液は、少しさらなるブラストが骨髄前駆体及び赤芽球前駆体とが混ざり合った穏やかに増加した芽細胞を示している。後者は、わずかに不規則な核輪郭及び最小の巨赤芽球様の変化を示している(ライトギムザ、1000x)(図5J)。インレットには、デリケートまたは微細なクロマチン、顕著な核小体、高いN:C比、及び乏しい好塩基性細胞質を示している2つの芽球が含まれている。トランスジェニックマウス脾臓のタッチプリパレーション(touch preparation)は、赤芽球前駆体が増加していることを示しており;それらのいくつかは、異常な核性及び随時の核橋を有する拡大サイズを示している(ライトギムザ、1000x)(図5K)。
すべてのデータは平均±標準誤差として提示した。統計計算は、Microsoft ExcelまたはGraphPad Prism分析ツールで行った。個別群間の差は対応のあるt検定で分析した。0.05未満のP値を統計的に有意であるとみなした。
Lin−HLA−DR−CD33+ MDSCはMDS一次BM検体及び自己由来赤芽球前駆体の直接抑制で増殖する。骨髄単核球(BM−MNC)を、MDS BM穿刺液(n=12)、同一年齢層の健康者のBM(n=8)、または非MDS癌患者(胸部4及びリンパ腫4)から単離し、フローサイトメトリーによってLIN−HLA−DR−CD33+MDSCの存在について分析した。MDS患者は、健康なドナーまたは非MDS癌患者(5%未満、図1A)と比較して、著しくより高いMDSC数を示した(中央値35.5%、P<0.0001)。MDS−MDSCが悪性MDSクローンから誘導されるか否かを測定するために、LIN−HLA−DR−CD33+ MDSCを、染色体5q[del(5q)]または7q[del(7q)]欠失を有するMDS検体から分取し、特定のプローブを使用して蛍光in situハイブリダイゼーション(FISH)によって分析した。
造血におけるS100A9Tgマウス由来のMDSCの役割を正確に詳細に記載するために、同一年齢層のWT HSC、S100A9Tg HSC、または雄のマウス由来の富化BM HSCの混合物(1:1の比率)と一緒に、致命的に放射線にさらされた(900cGy)雌のFVB/NJマウス中へ富化HSCを競合的養子移入(competitive adoptive transfer)した。雄雌SRY遺伝子発現PCRアプローチを使用して移植をモニターすると、すべてのマウスが80%を超える移植を経験した(図8)。移植(8週で、WTレシピエントにおいてWBCが3x103細胞/μL超と定義する)の後、WT HSCのレシピエントは、移植されていないWTマウスにおけるレベルと同等な(図5A)、BM由来のGr1+Cd11b+とHSC(図6A及び6C)の両方の割合を有していた。対照的に、S100A9Tg富化HSCによる養子移入は、HSCの割合の減少を伴うGFP発現Gr1+Cd11b+MDSC(図6B)を高い割合で生成させ、これらの結果は、我々の高齢のトランスジェニックマウスにおける観察と類似していた(図6C)。しかしながら、混合HSC集団を受容したマウスは、WT養子移入マウスのそれに近いMDSCの割合(約30%)を有していた。特に、約50%に近いMDSCがGFP発現を欠いており、WT HSPC(図6B)由来の起源(origination)を示しているが、残りのGFP+ MDSCはS100A9Tgドナー細胞由来であった。全MDSC集団はS100A9Tg養子移入マウスで観察されるレベルまで増加しなかったが、S100A9Tgドナー細胞を移植されたマウスで見出されたレベルまでHSCの割合は減少したことが観察された(図6C)。これらの所見は、S100A9Tgドナー細胞由来の活性化MDSCのより少ない集団は、造血の完全性の同等の障害をもたらすのに十分な抑制性活性を有していたことを示している。これらの所見は、混合供給源移植レシピエントが、S100A9TgまたはWTドナー細胞(図6D、6E、6F)を受容しているマウスに比べて重症度が中程度の血球減少症を有していた、末梢血球算定の逐次分析によって支持された。興味深いことに、混合ドナーレシピエントは移植後のHSCの割合がTg移植マウスと同じであったが、それらのWBC計数は、S100A9Tg HSCを移植されたマウスに比べてより高く、WT HSCレシピエントのレベルに比べてより低かった。同様に、貧血の発症は、S100A9Tgドナー細胞に対して混合レシピエントでは遅れた。これらの所見は、WTマウス由来の正常なHSCは部分的に造血を救助することができるが、時間と共に、S100A9Tgドナー細胞に由来するMDSCが蓄積することによって、造血は抑制される。
BM微小環境内の炎症性刺激は、MDSにおける前駆細胞の増殖及びアポトーシスを刺激する重要な生物学的シグナルと認識される。最近の集団研究は、慢性免疫刺激とMDS疾病素質との間の強い連関を示すことによって、更にこれを拡張した(Kristinsson,S.Y.,et al.2011.J Clin Oncol 29:2897−2903)。ニッチ内因性異常それ自体のみによって細胞の非自律的な様式でのMDSの発症を説明できる決定的な証拠は、乏しい。Raaijmakersと同僚は、BM微小環境の間葉成分におけるDicer1の欠失によって引き起こされる選択的な骨前駆細胞機能不全は、造血を混乱させ、そして骨髄形成異常の発症、続いて骨髄系に拘束された遺伝的異常の二次的生成へと導くのに十分である、ことを示した(Raaijmakers,M.H.,et al.2010.Nature 464:852−857)。
活性なカスパーゼ−1(表3)及びIL−1β生成(表4)を4つの集団:すなわち幹細胞(CD34+CD38−)、前駆細胞(CD34+CD38+)、赤芽球(CD71+)、及び骨髄細胞(CD33+)で評価した。平均蛍光強度(MFI)値を表3に示す。
Claims (27)
- (a)ヒトCD33の細胞外ドメイン、toll様受容体4(TLR4)の細胞外ドメイン、及び終末糖化産物受容体(RAGE)の細胞外ドメインから成る群より選択される少なくとも2つのS100A9結合部分、及び
(b)免疫グロブリンFc領域
を含む組換え融合タンパク質。 - 以下の式:すなわち
eCD33−eTLR4−Fc、
eCD33−eRAGE−Fc、
eTLR4−eRAGE−Fc、
eRAGE−eTLR4−Fc、
eCD33−eTLR4−eRAGE−Fc、
eCD33−eRAGE−eTLR4−Fc、
eTLR4−eCD33−eRAGE−Fc、
eRAGE−eCD33−eTLR4−Fc、
eTLR4−eRAGE−eCD33−Fc、及び
eRAGE−eTLR4−eCD33−Fc
から成る群より選択される式を含む請求項1記載の融合タンパク質であって、
式中「eCD33」はヒトCD33の細胞外ドメインを含み、
式中「eTLR4」はTLR4の細胞外ドメインを含み、
式中「eRAGE」はRAGEの細胞外ドメインを含み、
式中「Fc」は免疫グロブリンFc領域を含み、
そして式中「−」はペプチドリンカーまたはペプチド結合から成る、
前記融合タンパク質。 - ビオチン及びATPの存在下で、ビオチンリガーゼ(BirA)によってビオチン化され得るビオチン受容体ペプチドを更に含む請求項1または2記載の融合タンパク質。
- (a)ヒトCD33の細胞外ドメイン、toll様受容体4(TLR4)の細胞外ドメイン、及び終末糖化産物受容体(RAGE)の細胞外ドメインから成る群より選択されるS100A9結合部分、
(b)ビオチン及びATPの存在下で、ビオチンリガーゼ(BirA)によってビオチン化され得るビオチン受容体ペプチド、及び
(c)免疫グロブリンFc領域
を含む組換え融合タンパク質。 - 以下の式:すなわち
eCD33−Fc−Avi、
eTLR4−Fc−Avi、
eRAGE−Fc−Avi、
eCD33−eTLR4−Fc−Avi、
eCD33−eRAGE−Fc−Avi、
eTLR4−eRAGE−Fc−Avi、
eRAGE−eTLR4−Fc−Avi、
eCD33−eTLR4−eRAGE−Fc−Avi、
eCD33−eRAGE−eTLR4−Fc−Avi、
eTLR4−eCD33−eRAGE−Fc−Avi、
eRAGE−eCD33−eTLR4−Fc−Avi、
eTLR4−eRAGE−eCD33−Fc−Avi及び
eRAGE−eTLR4−eCD33−Fc−Avi
から成る群より選択される式を含む請求項4記載の融合タンパク質であって、
式中「eCD33」はヒトCD33の細胞外ドメインを含み、
式中「eTLR4」はTLR4の細胞外ドメインを含み、
式中「eRAGE」はRAGEの細胞外ドメインを含み、
式中「Fc」は免疫グロブリンFc領域を含み、
式中「Avi」は、ビオチン及びATPの存在下で、ビオチンリガーゼ(BirA)によってビオチン化され得る任意のビオチン受容体ペプチドを含み、
そして式中「−」はペプチドリンカーまたはペプチド結合から成る、
前記融合タンパク質。 - 前記ビオチン受容体ペプチドが、配列番号7のアミノ酸配列、または配列番号7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請求項3〜5のいずれか一つに記載の融合タンパク質。
- 前記ヒトCD33の細胞外ドメインが、前記可変領域のみを含む請求項1〜6のいずれか一つに記載の融合タンパク質。
- (a)前記ヒトCD33の可変細胞外ドメイン、及び
(b)免疫グロブリンFc領域
から実質的に成る組換え融合タンパク質。 - 前記ヒトCD33の細胞外ドメインが、配列番号1のアミノ酸配列、または配列番号1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請求項1〜8のいずれか一つに記載の融合タンパク質。
- 前記ヒトCD33の細胞外ドメインが、前記配列番号2のアミノ酸配列を含む請求項9記載の融合タンパク質。
- 前記ヒトCD33の可変領域が、配列番号3のアミノ酸配列、または配列番号3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請求項7〜8のいずれか一つに記載の融合タンパク質。
- 前記ヒトCD33の可変領域が、配列番号4のアミノ酸配列を含む請求項11記載の融合タンパク質。
- 前記ヒトTLR4の細胞外ドメインが、配列番号5のアミノ酸配列、または配列番号5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請求項1〜12のいずれか一つに記載の融合タンパク質。
- 前記RAGEの細胞外ドメインが、配列番号6のアミノ酸配列、または配列番号6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請求項1〜13のいずれか一つに記載の融合タンパク質。
- コア分子またはコア粒子にコンジュゲートされた請求項1〜14のいずれか一つに記載の2つ以上の融合タンパク質を含む多量体複合体。
- 前記コア分子がストレプトアビジンであり、前記2つ以上の融合タンパク質がビオチン化される請求項15記載の多量体複合体。
- 前記コア分子が、前記2つ以上の融合タンパク質と特異的に結合する抗体を含むリポソームである請求項15記載の多量体複合体。
- 前記抗体が、前記ビオチン受容体ペプチドと特異的に結合する請求項17記載の多量体複合体。
- 前記コア分子またはコア粒子にコンジュゲートされた2〜5つの融合タンパク質を含む請求項15〜18のいずれか一つに記載の多量体複合体。
- S100A9活性によって引き起こされるかまたは悪化する疾患または状態を治療する方法であって、請求項1〜18のいずれか一つに記載の融合タンパク質または請求項15〜19のいずれか一つに記載の多量体複合体を含む組成物を、前記治療を必要としている対象に対して投与することを含む、前記方法。
- 前記方法が、前記患者における感染、敗血症、またはそれらの組み合わせを治療することを含む請求項20記載の方法。
- 前記方法が、前記患者の自己免疫疾患を治療することを含む請求項20記載の方法。
- 前記方法が、前記患者の関節リウマチを治療することを含む請求項20記載の方法。
- 前記方法が、前記患者の癌を治療することを含む請求項20記載の方法。
- 前記方法が、前記対象の骨髄異形成症候群(MDS)を治療することを含む請求項20記載の方法。
- 対象の骨髄異形成症候群(MDS)を治療する方法であって、S100A9と結合して隔離する可溶性CD33融合体タンパク質を含む組成物の治療有効量を前記対象に対して投与することを含む、前記方法。
- S100A9がCD33に結合することを阻止する能力について候補薬剤をスクリーニングすることを含む、骨髄異形成症候群(MDS)を治療するための薬剤を同定する方法。
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