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Relapsed acute lymphoblastic leukemia (ALL), particularly with central nervous system (CNS) involvement, remains a major cause of treatment failure and is inadequately controlled by existing antibody-drug conjugates (ADCs) with tubulin inhibitors. To address this limitation, we developed IL-7Rα-targeted monoclonal antibodies and identified clone 577 as the lead candidate. Using this antibody, we generated ADCs conjugated with either monomethyl auristatin E (MMAE) or the highly potent DNA-damaging payload-PNU-159682 (PNU). In head-to-head comparisons, 577-PNU showed >50-fold greater potency than 577-MMAE in vitro and induced complete tumor regression in xenografts at a 20-fold lower dose. Additionally, 577-PNU provided durable systemic disease control and markedly reduced leukemic infiltration in the brain and spinal cord in both preventive and established murine CNS disease models, offering direct evidence of effective CNS penetration. Safety assessments demonstrated stable body weight, normal hematology and serum biochemistry, and no treatment-related pathologies. Collectively, these findings provide the first preclinical evidence that IL-7Rα-directed ADCs armed with DNA-targeting payload PNU-159682 can achieve durable elimination of systemic and CNS leukemia at tolerable doses, demonstrating both clinical feasibility and CNS disease control, and establishing a compelling rationale for their translational and clinical development in relapsed and refractory ALL.