zilovertamab (UC-961)

P2, N=5, Active, not recruiting, University of California, San Diego | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jul 2025 --> Jul 2026

Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking.

P2/3, N=62, Completed, Shanghai Jiaolian Drug Research and Development Co., Ltd | N=450 --> 62 | Trial completion date: Dec 2026 --> Sep 2024 | Recruiting --> Completed | Trial primary completion date: Jun 2025 --> Sep 2024

P2/3, N=450, Recruiting, Shanghai Jiaolian Drug Research and Development Co., Ltd | Trial primary completion date: Dec 2024 --> Jun 2025

P1, N=6, Terminated, University of California, San Diego | N=32 --> 6 | Trial completion date: Feb 2026 --> Oct 2024 | Recruiting --> Terminated | Trial primary completion date: Feb 2025 --> Oct 2024; Oncternal closing clinical trial operations.

P1/2, N=102, Completed, Oncternal Therapeutics, Inc | Active, not recruiting --> Completed

P2, N=90, Not yet recruiting, Shanghai Jiaolian Drug Research and Development Co., Ltd

P1, N=22, Completed, Barbara Parker, MD | Active, not recruiting --> Completed | Phase classification: P1b --> P1

The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.

P1, N=32, Recruiting, University of California, San Diego

P1/2, N=102, Active, not recruiting, Oncternal Therapeutics, Inc | Phase classification: P1b/2 --> P1/2

Co-culture of Jurkat-Lucia cells for 6 hours with the anti-CD20 mAb rituximab and MEC1 or MEC1-ROR1 cells induced Jurkat-Lucia cells to express a luciferase reporter gene under the control of an ISG54 minimal promoter fused to six NFAT response elements; this endowed the Jurkat-Lucia cells with high luminescence activity that was not observed in co-cultures of EC and TC without added mAb. ROR1 + CLL cells harboring del(17p) or mutations in TP53 (del(17p)/m TP53) and/or that were resistant to targeted therapies (e. g. , inhibitors of BTK or BCL2), were as susceptible to GE-zilovertamab-directed ADCC as were CLL cells without del(17p)/m TP53 from patients who had not had prior therapy. These data demonstrate that GE-zilovertamab can direct high-level ADCC lysis of ROR1-expressing neoplastic cells with greater activity than zilovertamab, encouraging development of clinical studies to evaluate GE-zilovertamab for therapy of patients with CLL or other ROR1-positive cancers.