癌症
分子生物学
癌细胞
癌症研究
生物
糖基化
靶向治疗
突变
流式细胞术
化学
细胞生物学
突变
生物化学
基因
遗传学
作者
Emanuela Guerra,Marco Trerotola,Valeria Relli,Rossano Lattanzio,Romina Tripaldi,Martina Ceci,Khouloud Boujnah,Ludovica Pantalone,Andrea Sacchetti,Kristina M. Havas,Pasquale Simeone,Nicole Travali,Patrizia Querzoli,Massimo Pedriali,Pietro Roversi,Manuela Iezzi,Nicola Tinari,Laura Antolini,Saverio Alberti
标识
DOI:10.1158/1535-7163.mct-22-0352
摘要
Abstract Next-generation Trop-2–targeted therapy against advanced cancers is hampered by expression of Trop-2 in normal tissues. We discovered that Trop-2 undergoes proteolytic activation by ADAM10 in cancer cells, leading to the exposure of a previously inaccessible protein groove flanked by two N-glycosylation sites. We designed a recognition strategy for this region, to drive selective cancer vulnerability in patients. Most undiscriminating anti–Trop-2 mAbs recognize a single immunodominant epitope. Hence, we removed it by deletion mutagenesis. Cancer-specific, glycosylation-prone mAbs were selected by ELISA, bio-layer interferometry, flow cytometry, confocal microscopy for differential binding to cleaved/activated, wild-type and glycosylation site–mutagenized Trop-2. The resulting 2G10 mAb family binds Trop-2–expressing cancer cells, but not Trop-2 on normal cells. We humanized 2G10 by state-of-the-art complementarity determining region grafting/re-modeling, yielding Hu2G10. This antibody binds cancer-specific, cleaved/activated Trop-2 with Kd < 10−12 mol/L, and uncleaved/wtTrop-2 in normal cells with Kd 3.16×10−8 mol/L, thus promising an unprecedented therapeutic index in patients. In vivo, Hu2G10 ablates growth of Trop-2–expressing breast, colon, prostate cancers, but shows no evidence of systemic toxicity, paving the way for a paradigm shift in Trop-2–targeted therapy.
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