癌症研究
T790米
表皮生长因子受体
医学
肺癌
埃罗替尼
表皮生长因子受体抑制剂
皮疹
酪氨酸激酶
癌症
受体
内科学
吉非替尼
作者
Sheri L. Moores,Mark L. Chiu,Barbara S. Bushey,Kristen Chevalier,Leopoldo Luistro,Keri Dorn,Randall J. Brezski,Peter Haytko,Thomas J. Kelly,Sheng‐Jiun Wu,Pauline L. Martin,Joost Neijssen,Paul W.H.I. Parren,Janine Schuurman,Ricardo M. Attar,Sylvie Laquerre,Matthew V. Lorenzi,Geoffrey M. Anderson
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2016-05-24
卷期号:76 (13): 3942-3953
被引量:200
标识
DOI:10.1158/0008-5472.can-15-2833
摘要
Abstract Non–small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor–binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942–53. ©2016 AACR.
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