Zenocutuzumab

Zenocutuzumab is a bispecific humanized IgG1 antibody containing two different Fab arms that target the extracellular domains of HER2 and HER3^[1]. Zenocutuzumab specifically binds to the HER3 receptor, blocks its interaction with the ligand, and inhibits downstream PI3K/AKT and MAPK/ERK signaling pathway activation^{[2, 3]}. Zenocutuzumab can be used to treat NRG1 fusion-positive cancers, which are oncogenic drivers of pancreatic cancer and other solid tumors^[4].

In vitro, treatment of homologous human bronchial epithelial cell lines (HBEC) expressing CD74-NRG1 or VAMP2-NRG1 fusions with Zenocutuzumab (0.001-1000nM) for 96h significantly inhibited cell growth. HBEC cells with NRG1 fusions were approximately 40,000-fold more sensitive to Zenocutuzumab than parental control cells^[5]. Zenocutuzumab (0.1-1000nM) treatment of HBEC-CD74NRG1, LUAD-0061AS3 and MDA-MB-175-VII cells dose-dependently reduced the phosphorylation of HER3, HER2 and HER4^[5].

In vivo, Zenocutuzumab (2.5-25mg/kg) treated with patient-derived xenograft (PDX) model mice by intraperitoneal injection inhibited tumor growth in a dose-dependent manner and caused tumor regression^[5].

References:
[1] Antonarelli G, Giugliano F, Corti C, et al. Research and clinical landscape of bispecific antibodies for the treatment of solid malignancies[J]. Pharmaceuticals, 2021, 14(9): 884.
[2] Yin L. Gene Editing in ErbB/HER Family-Mediated Cancer Immunology[J]. 2025.
[3] Bhagyalalitha M, Shankaranarayana A H, Kumar S A, et al. Advances in HER2-Targeted Therapies: From monoclonal antibodies to dual inhibitors developments in cancer treatment[J]. Bioorganic Chemistry, 2024: 107695.
[4] Schram A M, O'Reilly E M, O'Kane G M, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions[J]. 2021.
[5] Schram A M, Odintsov I, Espinosa-Cotton M, et al. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements[J]. Cancer Discovery, 2022, 12(5): 1233-1247.

Zenocutuzumab是一种双特异性人源化 IgG1 抗体，包含两个不同的Fab臂，靶向HER2和HER3的细胞外结构域^[1]。Zenocutuzumab通过特异性结合HER3受体，阻断其与配体的相互作用，抑制下游PI3K/AKT和MAPK/ERK信号通路激活^{[2, 3]}。Zenocutuzumab能够用于治疗NRG1融合阳性癌症，NRG1融合蛋白是胰腺癌和其他实体肿瘤的致癌驱动因素^[4]。

在体外，Zenocutuzumab（0.001-1000nM）处理表达CD74-NRG1或 VAMP2-NRG1融合的同源人支气管上皮细胞系（HBEC）96h，显著抑制了细胞的生长，具有NRG1融合的HBEC细胞对Zenocutuzumab的敏感性比亲本对照细胞高出约40000倍^[5]。Zenocutuzumab（0.1-1000nM）处理HBEC-CD74NRG1、LUAD-0061AS3和MDA-MB-175-VII细胞，剂量依赖性地降低了HER3、HER2和HER4的磷酸化^[5]。

在体内，Zenocutuzumab（2.5-25mg/kg）通过腹腔注射治疗患者来源异种移植（PDX）模型小鼠，以剂量依赖性方式抑制了肿瘤生长，引起了肿瘤消退^[5]。