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大学・研究所にある論文を検索できる 「小細胞肺癌における抗体薬物複合体の新規治療標的の探索」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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小細胞肺癌における抗体薬物複合体の新規治療標的の探索

四元, 拓真 東京大学 DOI:10.15083/0002007058

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 四元 拓真
本研究は治療パラダイムの変化に乏しい小細胞肺癌に対し、新規治療モダリティである
抗体薬物複合体(Antibody-Drug Conjugate, ADC)の標的となり得る分子を探索するため、
小細胞肺癌特異的に発現する細胞表面蛋白を計算生物学的に絞り込み、候補分子に対する
ADC を投与して in vitro における殺細胞性の解析を試みたものであり、下記の結果を得て
いる。
1.オープンソースのデータベースのマイクロアレイデータから Gene Ontology を用いて
細胞表面蛋白をコードする遺伝子を絞り込み、その発現を解析することで小細胞肺癌
株に高発現であり、また副作用低減のため正常臓器にて低発現の細胞表面蛋白として
DLK1 ,NRXN1, SYT1, TRPM8 を同定した。
2.実際に小細胞肺癌細胞株における細胞表面蛋白の高発現がフローサイトメトリーで確
認できた NRXN1, TRPM8 に関連して、各分子に対する 1 次抗体と、2 次抗体として
PNU を接合した抗体を secondary ADC としてこれらを高発現する小細胞肺癌細胞株
に添加したところ、NRXN1 を介した ADC で殺細胞性を発揮した。1 次抗体のみ、
secondary ADC のみでは殺細胞性は示されず、この傾向は NRXN1 を強制発現した
HEK293 細胞株でも同様であった。
3.NRXN1 を特異的にノックアウトした NRXN1 高発現の小細胞肺癌株に対しては、
NRXN1 を介した ADC の殺細胞性は明らかに低減され、逆の効果を示した。
4.実際に NRXN1 を介した ADC で細胞死が誘導されているかを確認する目的で
apoptosis assay を NRXN1 高発現、低発現細胞株を用いて行い、NRXN1 高発現細胞
株において 1 次抗体のみ、secondary ADC のみ、isotype control と secondary ADC
を添加した群に比して、抗 NRXN1 抗体と secondary ADC を添加した群において有
意に多くの割合で細胞死が誘導されていることを PI と Annexin-V 両染色後のフロー
サイトメトリーによる解析で確認した。
以上、本論文は小細胞肺癌株を含む NRXN1 高発現細胞株において、NRXN1 依存性に
NRXN1 を介した ADC が細胞毒性を示すことを明らかにした。小細胞肺癌に対する ADC
における既存の標的候補である DLL3 や TROP2 に加え、新たな治療標的として有望であ
る可能性があり、その機能解析や前臨床試験への応用など、さらなる研究に値すると考え
られる。
よって本論文は博士(医学 )の学位請求論文として合格と認められる。

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