Preclinical evaluation of the ROR1-targeting antibody-drug conjugates zilovertamab vedotin and VLS-211 against B-cell ALL patient-derived xenografts.

Although survival rates for acute lymphoblastic leukemia (ALL) have improved dramatically over the past 60 years, outcomes vary across different molecular subtypes and risk categories, and a significant number of patients remain difficult to treat. ROR1 is a receptor tyrosine kinase expressed in B-cell ALL, particularly in patients with TCF3::PBX1 gene rearrangements. ROR1 has served as the target of several immune-based therapies including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and CAR T-cell therapies. Here, we evaluated the ROR1-targeting ADCs zilovertamab vedotin (ZV, previously known as MK-2140 or VLS-101) and VLS-211 in vivo against a panel of ALL patient-derived xenografts with variable ROR1 expression. Both agents showed modest activity, which was dependent on ROR1 expression. Notably, we identified pediatric patients with TCF3::HLF gene fusions, which is a highly chemoresistant ALL subtype, as having some of the highest ROR1 expression in pediatric ALL and show that this subtype is susceptible to targeting ROR1 via ADC-based therapy. Given that ZV has a favorable toxicity profile in patients with hematological malignancies, it may have some utility in the treatment of very high-risk pediatric B-ALL, particularly cases with TCF3::HLF gene fusions.