ROR1 (Receptor Tyrosine Kinase-Like Orphan Receptor 1) is an oncofetal protein highly expressed during embryogenesis but largely absent in healthy adult tissues. It reappears in various cancers, including chronic lymphocytic leukemia (CLL), breast cancer, lung cancer, and pancreatic cancer, making it a promising therapeutic target. ROR1 promotes tumorigenesis by regulating cell survival, proliferation, and metastasis through Wnt5a signaling and interactions with other pathways like PI3K/AKT and NF-κB.
ROR1-targeting antibodies have emerged as a key focus in cancer immunotherapy. Monoclonal antibodies (e.g., cirmtuzumab) bind to ROR1’s extracellular domain, blocking pro-survival signaling and inducing antibody-dependent cellular cytotoxicity (ADCC). Bispecific antibodies, such as those engaging CD3 or PD-1. enhance T-cell-mediated tumor killing. Additionally, ROR1-directed CAR-T cells and antibody-drug conjugates (ADCs) are under preclinical and clinical evaluation.
Early-phase trials (Phase I/II) of ROR1 antibodies show encouraging safety and efficacy, particularly in CLL and mantle cell lymphoma. Challenges include managing on-target/off-tumor toxicity due to low ROR1 expression in some normal tissues (e.g., adipocytes) and addressing resistance mechanisms. Research also explores ROR1’s role as a diagnostic biomarker and its crosstalk with tumor microenvironments.
Overall, ROR1 antibodies represent a versatile therapeutic strategy, with ongoing efforts to optimize specificity, combinatorial regimens, and patient stratification.