Authors
Nathan El-Ghazzi, Tony Sourisseau, Vanessa Chaire, Tom Del Ben, Marie-Alix Derieppe, Lucile Vanhersecke, Christophe Rey, Alban Bessede, Jean-Max Pasquet, Antoine Italiano
Published in
Journal of hematology & oncology. Volume 19. Issue 1. Oct 16, 2026. Epub Oct 16, 2026.
Abstract
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.
PMID:
42888419
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.
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