組織交叉反應(yīng)（tissue cross reactivity，TCR）是單克隆抗體藥物開發(fā)過程中臨床前安全評(píng)價(jià)的重要組成部分。TCR試驗(yàn)的目的是發(fā)現(xiàn)單抗藥物和靶抗原以外表位結(jié)合，為體內(nèi)試驗(yàn)毒副作用的監(jiān)控提供參考。按照FDA、EMA和CFDA要求，TCR需在新藥臨床申請(qǐng)Ⅰ期臨床試驗(yàn)前完成。近年隨著單克隆抗體研發(fā)由鼠源型向全人源化單抗的轉(zhuǎn)變和發(fā)展，免疫組織化學(xué)在很多技術(shù)環(huán)節(jié)上出現(xiàn)了新的問題和挑戰(zhàn)。結(jié)合自身實(shí)際工作的經(jīng)驗(yàn)和近年來國內(nèi)外組織交叉反應(yīng)研究的進(jìn)展，探討并總結(jié)單抗藥物研發(fā)中TCR試驗(yàn)中的相多路徑體系技術(shù)難點(diǎn)的探索和研究經(jīng)驗(yàn)，期望能為進(jìn)一步提高我國TCR試驗(yàn)質(zhì)量，并增加TCR試驗(yàn)對(duì)體內(nèi)毒理學(xué)評(píng)價(jià)及安全用藥的參考價(jià)值提供一定的參考。

Tissue cross-reactivity (TCR) studies play an important role in the preclinical safety evaluation of monoclonal antibody (mAb) drugs. The objective of TCR studies is to find out off-target binding sites of mAbs, and provide valuable predictions for the toxicological evaluation and safety medication in vivo. According to the new drug application requirements of FDA, EMA and CFDA, TCR studies need to be carried out before Phase I clinic trails. As the origin of mAb drugs was transferred from murine antibodies to fully humanized antibodies in current years, immunohistochemical methods used in TCR studies were confronted with some new problems and challenges. Taking our own experiences and recent progress on TCR studies at home and abroad together, the authors summarized the recent exploration on technical difficulties of multipath system in TCR studies. This may provide valuable insight for further improving the quality of TCR studies and increase the predictive value of TCR studies for in vivo toxicological evaluation in China.

“十二五”重大專項(xiàng)定向擇優(yōu)（2015ZX09501004-002-006和2015ZX09501-007-003）；上海市新藥安全評(píng)價(jià)專業(yè)技術(shù)服務(wù)平臺(tái)（15DZ2290300）；上海市浦東新區(qū)科委CRO項(xiàng)目（PKF2014-C01）