AXL-directed antibody-drug conjugate therapy in soft-tissue sarcoma.

AXL is a membrane-accessible receptor tyrosine kinase and a potential antibody-drug conjugate (ADC) target, but its therapeutic relevance in soft-tissue sarcoma remains incompletely defined. We evaluated the AXL-directed pyrrolobenzodiazepine ADC ADCT-601/mipasetamab uzoptirine using a sarcoma tissue microarray, patient-derived cell lines, and patient-derived xenografts. AXL expression was broad but heterogeneous, with the highest histotype-level expression in myxofibrosarcoma and undifferentiated pleomorphic sarcoma. In the patient-linked tissue-microarray cohort, AXL H-score was not associated with metastasis-free or overall survival after clinicopathologic adjustment. ADCT-601 was substantially more potent than a non-targeting anti-gp120 control ADC carrying the same SG3199-containing payload. Free-payload sensitivity varied between cell lines, indicating that intrinsic payload susceptibility contributes to activity, while the payload-matched comparison supports an additional effect of AXL-mediated delivery. ADCT-601 induced cell-cycle perturbation, apoptosis, and γ-H2AX accumulation. Combination experiments identified enhanced activity with DNA damage-response inhibition, particularly ATR inhibition, and in vivo studies supported antitumor activity in two sarcoma xenograft models. These data support biomarker-enriched development of next-generation AXL-directed ADC strategies while emphasizing antigen heterogeneity and therapeutic-index optimization.