JP7368528B2 - 抗腫瘍抗原ナノボディ及びその核酸コード配列、並びにその使用 - Google Patents
抗腫瘍抗原ナノボディ及びその核酸コード配列、並びにその使用 Download PDFInfo
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Description
ウエスタンブロッティング(Western blotting)により、抗HLA-Gナノボディがヒトがん細胞株MDA-MB-231及びA549の細胞溶解物中のHLA-Gタンパク質を特定できることを証明し、
フローサイトメトリー(flow cytometric analysis)及び免疫細胞化学の分析により、抗HLA-Gナノボディが細胞膜上のHLA-Gタンパク質を特定できること、HLA-Gの発現及び細胞膜マーカーであるPan-カドヘリン(Pan-Cadherin)がMDA-MB-231及びA549細胞に共局在していることを証明し、及び、
免疫組織化学的染色(immunohistochemistry staining、IHC staining)により、抗HLA-G抗体がHLA-Gの発現を検出するために用いられることを証明する。
本明細書に記載の数値は、概算値である。全ての実験データは、その数値の±20%、好ましいは±10%、より好ましくは±5%の範囲を示す。
本実施例において、抗ヒト白血球抗原-G(human leukocyte antigen-G、HLA-G)ナノボディ(nanobody、NB)の製造プロセスは、以下の通りである。重鎖可変ドメイン(heavy chain variable domain、VHH)の生成プロセスは、以下の通りである。
本実施例において、競合酵素結合免疫吸着アッセイ(competitive enzyme linked immunosorbent assay、competitive ELISA)による抗HLA-GナノボディのHLA-G/キラー細胞免疫グロブリン様受容体の2つのIgドメイン及び長い細胞質尾部4(killer cell immunoglobulin like receptor、two Ig domains and long cytoplasmic tail 4、KIR2DL4)の軸遮断の測定の操作手順は、以下の通りである。
本実施例において、抗HLA-Gナノボディによるヒト乳がん細胞株MDA-MB-231(ATCC(American Type Culture Collection)から購入)に対するナチュラルキラー細胞(natural killer cell、NK cell)の細胞溶解(cytolysis)作用の向上効用を評価する実験プロセスは、以下の通りである。1×105のMDA-MB-231細胞を12ウェルプレートに接種し、一晩静置する。
本実施例において、抗HLA-Gナノボディのウエスタンブロッティング(Western blotting)の操作手順は、以下の通りである。プロテアーゼ阻害剤カクテルを含有するPRO-PREPタンパク質抽出溶液(iNtRON、台北、台湾)から細胞を取り、4℃で15分間激しく振とうした後、遠心分離をする。上清を回収し、Bio-Rad BCA試薬(Bio-Rad Hercules、CA、USA)を使用してタンパク質の濃度を測定する。30μgの各サンプルのライセートをSDS-ポリアクリルアミドゲルで電気泳動し、そして、PVDF膜にエレクトロブロッティングする。
本実施例において、抗HLA-Gナノボディのフローサイトメトリー(flow cytometric analysis)の操作手順は、以下の通りである。まず、HLA-G組換え蛋白(CAT#:TP305216、Origene)(0.2μg/ml、1ウェルあたり100μl)を96ウェルプレートに添加し、4℃で一晩コーティングする。翌日、コーティングバッファーを除去し、室温で3%のスキムミルクで2時間ブロッキングする。そして、PBST(0.05%のTweenをPBSに溶解した)で5回洗浄する。
本実施例において、抗HLA-Gナノボディの免疫細胞化学的分析(immunocytochemistry)の操作手順は、以下の通りである。腫瘍細胞(1×105)を6ウェルプレートのスライドガラスに接種し、一晩培養する。特定の処理を行った後、細胞を1%のパラホルムアルデヒド(paraformaldehyde)に固定し、PBSで洗浄し、0.5%のBSAを含有するPBSに0.1% Triton X-100を使用して30分間透過化させ、2%のBSAでブロッキングし、特異的抗体(2%のBSA/0.05%のTween-20を含有するPBS(PBST)で混合された)と作用させる。洗浄した後、細胞とフルオレセイン共役二次抗体とを一緒に作用させる。PBSTで洗浄し、退色剤及び4’,6-ジアミジノ-2-フェニルインドール(4’,6-diamidino-2-phenylindole、DAPI)を含有する水溶性の封入剤で封入する。Leica TCS SP8 X共焦点顕微鏡(Leica)によって画像を分析する。
本実施例において、抗HLA-Gナノボディの免疫組織化学的染色(immunohistochemistry staining、IHC staining)の操作手順は、以下の通りである。ヒトの胎盤サンプルを10%のホルムアルデヒドで固定し、パラフィンに包埋する。切片(厚さ=3μm)をヘマトキシリン及びエオジンによって染色する。免疫組織化学について、99℃のマイクロ波によって抗原賦活化(antigen retrieval)を行う。切片をH2O2で洗浄して20分間作用させることにより、内因性ペルオキシダーゼを遮断する、そして、5%のBSAに30分間浸漬し、切片及び一次抗体を4℃で一晩作用させる。
ウエスタンブロッティング(Western blotting)により、抗HLA-Gナノボディがヒトがん細胞株MDA-MB-231及びA549の細胞溶解物中のHLA-Gタンパク質を特定できることを証明し、
フローサイトメトリー(flow cytometric analysis)及び免疫細胞化学の分析により、抗HLA-Gナノボディが細胞膜上のHLA-Gタンパク質を特定できること、HLA-Gの発現及び細胞膜マーカーであるPan-カドヘリン(Pan-Cadherin)がMDA-MB-231及びA549細胞に共局在していることを証明し、及び、
免疫組織化学的染色(immunohistochemistry staining、IHC staining)により、抗HLA-G抗体がHLA-Gの発現を検出するために用いられることを証明する。
Claims (8)
- ヒト白血球抗原-G(human leukocyte antigen-G、HLA-G)に特異的に結合する抗腫瘍抗原ナノボディであって、
配列番号1、配列番号2、及び配列番号3からなる群から選ばれるアミノ酸配列であることを特徴とする、
抗腫瘍抗原ナノボディ。 - 前記HLA-Gと前記HLA-Gの受容体との相互作用及び/又は結合を遮断し、
前記受容体は、キラー細胞免疫グロブリン様受容体の2つのIgドメイン及び長い細胞質尾部4(killer cell immunoglobulin like receptor、two Ig domains and long cytoplasmic tail 4、KIR2DL4)、又は白血球免疫グロブリン様受容体サブファミリーBメンバー1(leukocyte immunoglobulin-like receptor subfamily B member 1、LILRB1)であることを特徴とする、
請求項1に記載の抗腫瘍抗原ナノボディ。 - 請求項1又は2に記載の抗腫瘍抗原ナノボディのアミノ酸配列をコードする単離された核酸であって、
配列番号4、配列番号5、配列番号6、及びそれらの任意の組み合わせからなる群から選ばれるヌクレオチド配列を含むことを特徴とする、
単離された核酸。 - 請求項1又は2に記載の抗腫瘍抗原ナノボディ、及び医薬上許容可能な担体を含むことを特徴とする、
医薬組成物。 - がん及び免疫関連疾患を治療するための医薬品を製造するための請求項1又は2に記載の抗腫瘍抗原ナノボディの使用。
- サンプルに請求項1又は2に記載の抗腫瘍抗原ナノボディを添加することを含み、
前記サンプルは、血液、尿液、痰液、唾液又は体液であることを特徴とする、
HLA-Gの発現レベルを検出するための方法。 - 請求項1に記載の抗腫瘍抗原ナノボディと、フラグメント結晶化可能領域(fragment crystallizable region、Fc region)とを含み、
前記抗腫瘍抗原ナノボディは、前記フラグメント結晶化可能領域と共役していることを特徴とする、
抗体共役物。 - 請求項1に記載の抗腫瘍抗原ナノボディと、第2の抗体とを含み、
前記抗腫瘍抗原ナノボディと前記第2の抗体との共役により、二重特異性T細胞エンゲージャー(bispecific T-cell engager、BiTE)、三重特異性T細胞エンゲージャー(triple specific T-cell engager、TriTE)、二重特異性キラー細胞エンゲージャー(bispecific killer cell enager、BiKE)、三重特異性キラー細胞エンゲージャー(triple specific killer cell engager、TriKE)、又は任意の二重特異性抗体を形成することを特徴とする、
抗体共役物。
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