HemaSphere · Published 2026-07-01 · DOI 10.1002/hem3.70438
Christopher M. Smith, Ben Watts, Kathryn Evans, Hansen Kosasih, Chelsea Mayoh, Stephen W. Erickson, Eric J. Earley, Steven Neuhauser, Timothy M. Stearns, Vivek M. Philip, Jeffrey H. Chuang, Charles E. de Bock, Edward P. Bowman, Katti A. Jessen, Emily L. Jocoy, Carol J. Bult, Beverly A. Teicher, Malcolm A. Smith, Richard B. Lock
Abstract 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.
Abstract from DOAJ. Public domain (CC0 1.0).
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Smith, C., Watts, B., Evans, K., et al. (2026). Preclinical evaluation of the ROR1‐targeting antibody–drug conjugates zilovertamab vedotin and VLS‐211 against B‐cell ALL patient‐derived xenografts. HemaSphere. https://doi.org/10.1002/hem3.70438