岩藻糖基化
肺癌
抗体依赖性细胞介导的细胞毒性
抗体
C-Met公司
癌症研究
体内
受体
表皮生长因子受体
表皮生长因子受体抑制剂
下调和上调
化学
医学
免疫学
单克隆抗体
生物
内科学
生物化学
聚糖
生物技术
糖蛋白
肝细胞生长因子
基因
作者
Katharine D. Grugan,Keri Dorn,Stephen Jarantow,Barbara S. Bushey,José R. Pardinas,Sylvie Laquerre,Sheri L. Moores,Mark L. Chiu
出处
期刊:mAbs
[Informa]
日期:2016-10-27
卷期号:9 (1): 114-126
被引量:57
标识
DOI:10.1080/19420862.2016.1249079
摘要
Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met (JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Met versions of JNJ-61186372 identified that the Fc-activity of JNJ-61186372 is mediated by binding of the anti-EGFR arm and required for inhibition of EGFR-driven tumor cells. In a tumor model driven by both EGFR and c-Met, treatment with Fc-silent JNJ-61186372 or with c-Met single-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is essential for maximal tumor inhibition. Moreover in this same model, downregulation of both EGFR and c-Met receptors was observed upon treatment with Fc-competent JNJ-61186372, suggesting that the Fc interactions are necessary for down-modulation of the receptors in vivo and for efficacy. These Fc-mediated activities, in combination with inhibition of both the EGFR and c-Met signaling pathways, highlight the multiple mechanisms by which JNJ-61186372 combats therapeutic resistance in EGFR mutant patients.
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