Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells.
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DOI：
10.1080/19420862.2016.1249079
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发表时间：
2017-01
期刊：
影响因子：
5.3
通讯作者：
Chiu ML
中科院分区：
文献类型：
--
作者：
Grugan KD;Dorn K;Jarantow SW;Bushey BS;Pardinas JR;Laquerre S;Moores SL;Chiu ML
表皮生长因子受体（EGFR）突变型非小细胞肺癌通过多种机制（包括c-Met受体途径激活）获得对EGFR酪氨酸激酶抑制剂的耐药性。我们生成了一种靶向EGFR和c-Met的双特异性抗体（JNJ-61186372），证明在野生型和突变型EGFR环境中具有c-Met通路激活的抗肿瘤活性。JNJ-61186372经工程改造具有低岩藻糖基化（<10%），导致抗体依赖性细胞介导的细胞毒性和FcγRIIIa结合增强。使用JNJ-61186372的单臂EGFR或c-Met版本进行的体外和体内研究发现，JNJ-61186372的Fc活性由抗EGFR臂的结合介导，并且是抑制EGFR驱动的肿瘤细胞所必需的。在EGFR和c-Met共同驱动的肿瘤模型中，与JNJ-61186372给药相比，Fc沉默JNJ-61186372或c-Met单臂抗体给药降低了肿瘤生长抑制，表明JNJ-61186372的Fc功能对于最大肿瘤抑制至关重要。此外，在该相同模型中，在用具有Fc活性的JNJ-61186372处理后观察到EGFR和c-Met受体下调，表明Fc相互作用是体内受体下调和疗效所必需的。这些Fc介导的活性与EGFR和c-Met信号传导途径的抑制相结合，突出了JNJ-61186372在EGFR突变患者中对抗治疗耐药性的多种机制。
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.