Anti-ROR1 Antibody (Zilovertamab)

ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1) is a receptor tyrosine kinase–like orphan receptor belonging to the ROR family. It is a type I transmembrane protein with an extracellular ligand‑binding domain and an intracellular tyrosine kinase–like region. During embryonic development, ROR1 is highly expressed and participates in the formation of multiple organs as well as in cell migration and differentiation; in contrast, its expression in normal adult tissues is very low or almost undetectable. However, in a variety of malignancies—such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and certain solid tumors (including triple‑negative breast cancer and lung adenocarcinoma)—ROR1 is abnormally overexpressed and is therefore regarded as a typical "onco‑fetal antigen."
From a cellular localization perspective, ROR1 is mainly distributed on the surface of tumor cell membranes. Its extracellular domain can serve as a binding target for antibodies, while its intracellular tyrosine kinase–like domain can regulate downstream signaling through noncanonical pathways such as Wnt5a–ROR1, including PI3K/AKT and Rho GTPases. In this way, it promotes tumor cell survival, proliferation, and migration and helps maintain stem cell–like properties. This mechanism makes ROR1 a tumor‑associated target with significant potential for drug development.
Zilovertamab (formerly known as Cirmtuzumab, development code UC‑961) is a humanized monoclonal antibody directed against ROR1. It has the typical structure of a full‑length IgG1, consisting of two heavy chains and two light chains. This antibody displays high affinity and high specificity; it can bind to the extracellular domain of ROR1 on the surface of tumor cell membranes, thereby blocking noncanonical Wnt signaling pathways such as Wnt5a–ROR1 and inhibiting downstream signaling related to cell survival, proliferation, and migration. At the same time, its Fc region can mediate activation of effector cells and the complement system, directly eliminating ROR1‑positive tumor cells.
At present, Zilovertamab is mainly being investigated for the treatment of hematologic malignancies, with a focus on ROR1‑high B‑cell cancers such as chronic lymphocytic leukemia and mantle cell lymphoma. Its potential application in certain ROR1‑positive solid tumors (e.g., triple‑negative breast cancer and lung cancer) is also being explored. The antibody can be used as monotherapy or in combination with BTK inhibitors and other anticancer drugs, with the aim of providing patients with ROR1‑positive tumors a highly targeted new therapeutic strategy that has minimal impact on normal adult tissues. In addition, Zilovertamab is often used as the antibody component in the construction of antibody–drug conjugates (ADCs), such as Zilovertamab vedotin (F1041), to achieve precise drug delivery to tumor cells.