Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements.
Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements.
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DOI：
10.1158/2159-8290.cd-21-1119
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发表时间：
2022-05-02
期刊：
影响因子：
28.2
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中科院分区：
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NRG1重排是实体瘤中反复出现的致癌驱动因素。NRG1与HER3结合，导致与其他HER/ERBB激酶的异源二聚化，增加下游信号转导，并导致肿瘤发生。因此，以ERBBS为靶点是治疗这些癌症的一种策略。我们研究了Zenocutuzumab(Zeno，MCLA-128)，一种ADCC增强的抗HER2xHER3双特异性抗体，在NRG1融合阳性的同基因和患者来源的细胞系和异种移植模型中。Zeno抑制HER3和AKT的磷酸化，诱导凋亡标志物的表达，并抑制细胞生长。三名化疗耐药的NRG1融合阳性转移性癌症患者接受了Zeno治疗。两名ATP1B1-NRG1阳性的胰腺癌患者症状、生物标志物和放射学反应迅速，并持续治疗超过12个月。一名CD74-NRG1阳性的非小细胞肺癌患者，在包括阿法替尼在内的六种先前的系统治疗中取得进展，对治疗迅速做出部分反应。用Zeno同时靶向HER2和HER3是NRG1融合阳性癌症患者的一种新的治疗范例。
NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno, MCLA-128), an ADCC-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three chemotherapy-resistant NRG1 fusion-positive metastatic cancer patients were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses, and remained on treatment for over 12 months. A CD74-NRG1-positive NSCLC patient who had progressed on six prior lines of systemic therapy including afatinib responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers.