Zilovertamab is a humanized monoclonal antibody that inhibits the tumor promoting activity of the cancer stem cell antigen ROR1 [1]. Zilovertamab can inhibit ROR1-signaling and cancer-stemness gene expression in cancer cells, and impair metastases [2]. Zilovertamab has been widely used to inhibit the proliferation of various cancer cells and is employed in the development of combined therapies to effectively suppress tumor invasion[3].
In vitro, Zilovertamab (50μg/ml) treatment for 72 hours significantly inhibited the proliferation of CaOV3, CaOV3CisR and PEO1 cells[4]. Treatment with 20μg/ml Zilovertamab for 24 hours can inhibit the release of MMP-9 by chronic lymphocytic leukemia (CLL) cells promoted by Wnt5a[5]. Treatment with 10μg/ml Zilovertamab for 4 days can inhibit the proliferation of mantle cell lymphoma (MCL) cells promoted by Wnt5a and reduce the proportion of cells in the S/G2 phase[6].
In vivo, Zilovertamab treatment via daily intraperitoneal injection at a dose of 1mg/kg for 7 days significantly reduced the burden of leukemia cells in Rag2−/−γc−/− mice[7]. Zilovertamab (10mg/kg) was administered intravenously once every two weeks for a total of 6 weeks, which significantly inhibited the occurrence of lung metastasis in mice bearing breast cancer patient-derived xenografts (PDX) and markedly reduced the number of metastatic lesions[8].
References:
[1] Lee H J, Choi M Y, Siddiqi T, et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL)[J]. 2022.
[2] Shatsky R A, Batra-Sharma H, Helsten T, et al. A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer[J]. Breast Cancer Research, 2024, 26(1): 32.
[3] Hasan M K, Widhopf II G F, Kipps T J. Combined Therapy of Zanubrutinib and Zilovertamab in the Inhibition of Invasive Capability of Chronic Lymphocytic Leukemia Cells[J]. Blood, 2023, 142: 6517.
[4] Liu D, Kaufmann G F, Breitmeyer J B, et al. The anti-ROR1 monoclonal antibody zilovertamab inhibits the proliferation of ovarian and endometrial cancer cells[J]. Pharmaceutics, 2022, 14(4): 837.
[5] Hasan M K, Widhopf II G F, Ghia E M, et al. Wnt5a induces ROR1 dependent NF-κB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia: CHRONIC LYMPHOCYTIC LEUKEMIA[J]. Leukemia, 2025, 39(7): 1661-1669.
[6] Yu J, Chen Y, Chen L, et al. Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma[J]. Oncotarget, 2018, 9(37): 24731.
[7] Yu J, Chen L, Cui B, et al. Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib[J]. Leukemia, 2017, 31(6): 1333-1339.
[8] Zhang S, Zhang H, Ghia E M, et al. Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody[J]. Proceedings of the National Academy of Sciences, 2019, 116(4): 1370-1377.