JP2019517271A - アネキシンのコアドメイン、並びに抗原送達及びワクチン接種におけるその使用 - Google Patents
アネキシンのコアドメイン、並びに抗原送達及びワクチン接種におけるその使用 Download PDFInfo
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- JP2019517271A JP2019517271A JP2018564358A JP2018564358A JP2019517271A JP 2019517271 A JP2019517271 A JP 2019517271A JP 2018564358 A JP2018564358 A JP 2018564358A JP 2018564358 A JP2018564358 A JP 2018564358A JP 2019517271 A JP2019517271 A JP 2019517271A
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Abstract
Description
配列は、以下の通りである:
C57BL/6マウスは、Jackson Laboratory社から購入した。全てのマウスは、特定病原菌不在施設で保持した。
組換えマウスGM-CSFを使用してBM前駆細胞のBMDCへの分化のために、1×106個の細胞を、24ウェルプレート中でRPMI 1640完全培地(10%のFCS、10 U/mlのペニシリン/ストレプトマイシン、300 mg/1 L-グルタミン、20 ng/mlのGM-CSF(Immunotools社))中で1×106個の細胞/mlの密度で播種した。2日後に、その培地を新しい培地により置き換えた。4日後に、その培地の半分を取り除き、新しい培地により置き換えた。実験は、分化の7日〜8日後に実施した。
マウス(m)AnxA1-OVA-pET41aプラスミドを、ニワトリオボアルブミン(OVA、NM_205152又はNP_990483、それぞれアミノ酸140から)を、C末端FLAGタグ、PreScissionプロテアーゼ開裂部位、及びプロテインAタグを有する改変されたpET41a中にクローニングすることにより作製した。さらに、2つのフレキシブルなリンカー及びタバコエッチウイルス(TEV)開裂部位を、mAnxA1とOVAとの間に導入した。連続的なPCRを、以下のプライマーを使用して実施した:
Fw_1:5'GGCGGAGGTTCAGGCGGAGGTTCAGATCAAGCCAGAGAGCTCATC 3';(配列番号9)、
Fw_2: 5'GAAAACTTGTATTTCCAGGGCGGCGGAGGTTCAGGCG 3';(配列番号10)、
Fw_3: 5'GGATCCGGCGGAGGTTCAGGCGGAGGTTCAGAAAACTTGTATTTCCAGGGCGG 3'(配列番号11)、及び、
Rev: 5'GGATCCAGGGGAAACACATCTGCCAAAG 3'(配列番号12)。
C57BL/6野生型マウス由来の2×105個のBMDCを、500 nM若しくは示された量の組換えオボアルブミン(OVA、Sigma社)、又はアネキシンコアドメイン-OVA融合タンパク質と一緒にインキュベートした。8時間〜12時間後に、DCをPBSで洗浄し、MHCクラスI中のOVA由来ペプチドSIINFEKLに対する蛍光標識された抗体(抗体25-D1.16、eBioscience社)と一緒にインキュベートした。SIINFEKL陽性細胞を、FACS(FACS-Canto、Becton-Dickinson社)において検出した。
C57BL/6野生型マウス由来の2×105個のBMDCを、500 nM若しくは示された量の組換えオボアルブミン(OVA、Sigma社)、又はアネキシンコアドメイン-OVA融合タンパク質と一緒にインキュベートした。12時間後に、1×106個の磁気的に精製(Easysep、Stemcell Technologies社)された、OT-Iマウス又はOT-IIマウスのそれぞれの脾臓由来のCD8陽性T細胞又はCD4陽性T細胞を上記DC培養物に添加した。1日〜2日後(インターロイキン-2)、又は3日〜5日後(インターフェロン-γ)に、示されたサイトカインは、培養上清中でELISA(Becton-Dickinson社)によって測定された。
LRP-1の種々のアネキシン(アネキシンA1、A5、及びA13)への結合の親和性の測定のために、装置A100(ATTANA社)を使用した。LRP-1を、製造業者の使用説明書に従ってLNBカルボキシチップ上に固定化させた。これを達成するために、最初に該チップを、製造業者の使用説明書に従ってEDC/SulfoNHSを用いて活性化させ、次いで酢酸ナトリウムバッファー(pH 4.0)中の精製LRP1(5 μg/ml〜15 μg/ml)を、そのチップ上に70 Hz〜100 Hzでの周波数の増加が得られるまで注入した。次いで、該チップ上の残りの結合スポットを、エタノールアミンの2回の注入を用いて飽和させ、該チップをPBS中で緩衝させた。種々のアネキシンと一緒にインキュベートするために、アネキシンを2 mMのカルシウムを有するPBS中で6種の異なる濃度で調製し、3回反復で測定した。それぞれのアネキシンの注入後に、該チップは、次のアネキシンの注入の前に5 mMのEDTA/PBS及び3 MのNaClで再生させた。
アネキシンへの結合についての試験のために、推定受容体分子、その断片、又は融合タンパク質(例えば、LRP-11、単独のLRP-1ドメイン、又はデクチン-1 Fcタンパク質)を、コーティングバッファー(炭酸塩−重炭酸塩−1.5 gのNa2CO3、2.93 gのNaHCO3、蒸留水、1リットル、pH 9.6まで)中で10 μg/mlでELISAプレート上に固定化する。洗浄(3×PBS Tween 0.01%)及びブロッキング(PBS中の1%のカゼイン)の後に、種々の濃度の組換えアネキシンを、ウェル中で2時間にわたりインキュベートし、引き続き5回の洗浄工程(PBS-Tween 0.05%)を行う。次いで、結合されたアネキシンは、該組換えアネキシンタンパク質に適した二次試薬(例えば、セイヨウワサビペルオキシダーゼ(HRP)標識された二次抗体又はビオチン標識された二次抗体と共にストレプトアビジン標識されたHRP)により検出され、それらは、ELISAプレートリーダー中で適切な基質(例えば、OPD)との反応性によって測定される。該アッセイはまた、種々のアネキシンをプレート上に固定化し、そして組換え受容体分子、その断片、又は融合タンパク質(例えば、LRP-11、単独のLRP-1ドメイン、又はデクチン-1 Fcタンパク質)でプロービングすることによっても実施することができる。
表面プラズモン共鳴(SPR)は、受容体リガンド相互作用をリアルタイムで解析し、結合の親和性及び動態を把握する上での有用なツールである。SPRは、アナライトと呼ばれるリガンドと受容体との会合及び解離の動態を測定するための技術である。アナライト又は受容体は、金被膜を有するセンサチップ上に固定化され得る。どちらが固定化されているかに応じて、アナライト及び受容体のどちらか一方との会合は、金被膜との接触において層の屈折率の変化を引き起こす。これは、表面層での屈折率の変化として測定され、SPRシグナルとして共鳴単位(RU)で記録される。デクチン-1で被覆された表面の調製のために、デクチン-1を、10 μl/分の流速で固定化した。そのCM5チップを、N-エチル-N'-(ジエチルアミノプロピル)-カルボジイミド(EDC)及びN-ヒドロキシスクシンイミド(NHS)の混合物を10分間にわたり注入することにより活性化し、そして酢酸バッファー(pH 5.5)中の100 μg/mL及び10 μg/mLのデクチン-1を7分間にわたり注入することにより官能化させた。次いで、残りの活性化されたカルボキシル基を、1 Mのエタノールアミンを10分間にわたり注入することにより封鎖した。対照フローセルを、上記のようにEDC/NHSに続きエタノールアミンで処理した。種々のアネキシンの濃度勾配を、デクチン-1で官能化された表面上に10 μL/分で注入し、60秒間の時間にわたり接触させ、300秒間の時間にわたり解離させ、引き続き100 mMのメチル-α-D-マンノピラノシドを使用して30 μL/分で30秒間にわたり再生させた。実験データを、Biacore S20 T100評価ソフトウェアを使用して解析した。アネキシン−デクチン-1複合体相互作用についての1:1相互作用モデルに基づく動態解析は、Scrubber2(BioLogic Software社、オーストラリア、キャンベル)を使用して実施した。
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図1A
anti-MHC-SIINFEKL 抗MHC-SIINFEKL
図1B
o/n オーバーナイト
% MHC I-SIINFEKL Positive cells MHC I-SIINFEKL陽性細胞の%
図2A
CD8+ T cells CD8陽性T細胞
Interferon-γ secretion インターフェロン-γ分泌
図3A
CD4+ T cells CD4陽性T細胞
Interleukin-2 secretion インターロイキン-2分泌
図4A
CD4+ T cells CD4陽性T細胞
Interferon-γ secretion インターフェロン-γ分泌
図4B
peptide ペプチド
図5
Frequency 周波数
mAnxA core mAnxAコア
Time (sec) 時間(秒)
図6
Absorbance 吸光度
Annexin-I アネキシン-I
Annexin-V アネキシン-V
Dectin1-hFc デクチン1-hFc
Response[RU](O=baseline) 応答(RU)(0=基線)
Annexin A1 アネキシンA1
Annexin A1 core domain アネキシンA1コアドメイン
Annexin A5 アネキシンA5
Annexin A13 アネキシンA13
Time (s) 時間(秒)
(continued) (続き)
図7
Hono sapiens ホモ・サピエンス
Ciona intestinalis and C. savignyi カタユウレイボヤ及びユウレイボヤ
Drosophila melanogaster キイロショウジョウバエ
Bombyx mori カイコ
Caenorhabditis elegans カエノラブディティス・エレガンス
Schistosoma mansoni About 9 proteins マンソン住血吸虫 約9タンパク質
Dictyostelium discoideum キイロタマホコリカビ
Viridiplantae 緑色植物亜界
Giardia lamblia About 7 proteins ランブル鞭毛虫 約7タンパク質
Protein length (amino acids) タンパク質長(アミノ酸)
図8
(continued) (続き)
図9
Anx-OVA(400 pMol or] OVA(400 pMol) Anx-OVA(400 pMol)又はOVA(400 pMol)
Tetramer staining 四量体染色
7d 7日
wt 野生型
OVA-specific CD8+ T cells[%] OVA特異的CD8陽性T細胞(%)
図10
Anx-OVA fusionprotein, DNA-sequence Anx-OVA融合タンパク質、DNA配列
Anx-OVA fusionprotein, aminoacid-sequence Anx-OVA融合タンパク質、アミノ酸配列
huAnxA1 Core huAnxA1コア
flexible Linker フレキシブルなリンカー
ovalbumin (OVA) オボアルブミン(OVA)
Claims (12)
- 配列番号1〜配列番号3及び配列番号6〜配列番号8の群から選択される配列中に含まれるコアドメインのアミノ酸配列を含む、又は配列番号1〜配列番号3及び配列番号6〜配列番号8の群から選択される配列中に含まれるアネキシンコアドメインのアミノ酸配列と少なくとも50%同一であるアミノ酸配列を含む、単離されたアネキシンコアドメイン。
- 少なくとも1つの請求項1に記載のアネキシンコアドメイン(i)と、MHC又はHLAにより提示される少なくとも1つの抗原性ペプチド(ii)とを含む、タンパク質結合物又は融合タンパク質。
- 前記抗原は、βhCG、gp100又はPmel17、HER2/neu、WT1、メソテリン、CEA、gp100、MART1、TRP-2、NY-BR-1、NY-CO-58、MN(gp250)、イディオタイプ、チロシナーゼ、テロメラーゼ、SSX2、MUC-1、MART1、melan-A、NY-ESO-1、MAGE-1、MAGE-3、MAGE-A3、及び高分子量メラノーマ関連抗原(HMW-MAA)からなる群から選択されるタンパク質に由来する、請求項2に記載のタンパク質結合物又は融合タンパク質。
- 前記結合物又は前記融合タンパク質は、共刺激性分子若しくはその免疫原性断片、又は共刺激性の第2のペプチド配列に更に結合/融合されている、請求項2又は3に記載のタンパク質結合物又は融合タンパク質。
- 請求項1〜4のいずれか一項に記載の融合タンパク質をコードする核酸。
- 前記抗原のコーディング配列は、βhCG、gp100又はPmel17、HER2/neu、WT1、メソテリン、CEA、gp100、MART1、TRP-2、NY-BR-1、NY-CO-58、MN(gp250)、イディオタイプ、チロシナーゼ、テロメラーゼ、SSX2、MUC-1、MART1、melan-A、NY-ESO-1、MAGE-1、MAGE-3、MAGE-A3、及び高分子量メラノーマ関連抗原(HMW-MAA)からなる群から選択されるタンパク質に由来する抗原をコードしている、請求項5に記載の核酸。
- 前記コーディング配列は、少なくとも1つのDC刺激性の核酸配列に融合されている、請求項5又は6に記載の核酸。
- 請求項5〜7のいずれか一項に記載の核酸を発現する組換え発現ベクター。
- 請求項2〜4のいずれか一項に記載のタンパク質結合物若しくは融合タンパク質、又は請求項5〜7のいずれか一項に記載の核酸、又は請求項8に記載の発現ベクターと、担体とを含む、医薬組成物。
- ワクチンである、請求項9に記載の医薬組成物。
- 被験体における感染性疾患又は癌の治療又は予防において使用するための、請求項9又は10に記載の医薬組成物。
- 被験体における感染性疾患又は癌を治療又は予防する方法であって、前記被験体に、請求項9又は10に記載の医薬組成物を投与することを含む、方法。
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BJORN LINKE ET AL.: "The Tolerogenic Function of Annexins on Apoptotic Cells Is Mediated by the Annexin Core Domain", THE JOURNAL OF IMMUNOLOGY, vol. 194, JPN7021001548, 2015, pages 5233 - 5242, XP055240591, ISSN: 0004500966, DOI: 10.4049/jimmunol.1401299 * |
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SI3468621T1 (sl) | 2023-01-31 |
CN109328077A (zh) | 2019-02-12 |
US10947283B2 (en) | 2021-03-16 |
CA3027011A1 (en) | 2017-12-14 |
DK3468621T3 (da) | 2022-12-05 |
WO2017211964A1 (en) | 2017-12-14 |
ES2933825T3 (es) | 2023-02-14 |
FI3468621T3 (fi) | 2023-01-13 |
US20210230238A1 (en) | 2021-07-29 |
EP3468621B1 (en) | 2022-09-21 |
US20190144513A1 (en) | 2019-05-16 |
US11851463B2 (en) | 2023-12-26 |
HRP20221372T1 (hr) | 2023-01-06 |
HUE060537T2 (hu) | 2023-03-28 |
LT3468621T (lt) | 2022-12-27 |
EP3468621A1 (en) | 2019-04-17 |
PT3468621T (pt) | 2022-12-21 |
PL3468621T3 (pl) | 2023-01-30 |
JP7377604B2 (ja) | 2023-11-10 |
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