AXL-directed antibody–drug conjugate therapy in soft-tissue sarcoma
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.
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BibTeX
@article{elghazzi2026axldirected,
title = {{AXL-directed antibody–drug conjugate therapy in soft-tissue sarcoma}},
author = {Nathan El-Ghazzi and Tony Sourisseau and Vanessa Chaire and Tom del Ben and Marie-Alix Derieppe and Lucile Vanhersecke and Christophe Rey and Alban Bessede and Jean-Max Pasquet and Antoine Italiano},
journal = {Journal of Hematology and Oncology},
year = {2026},
month = oct,
doi = {10.1186/s13045-026-01851-1},
url = {https://hal.science/hal-05805095v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AXL-directed antibody–drug conjugate therapy in soft-tissue sarcoma
AU - Nathan El-Ghazzi
AU - Tony Sourisseau
AU - Vanessa Chaire
AU - Tom del Ben
AU - Marie-Alix Derieppe
AU - Lucile Vanhersecke
AU - Christophe Rey
AU - Alban Bessede
AU - Jean-Max Pasquet
AU - Antoine Italiano
PY - 2026
DA - 2026/10/16
JO - Journal of Hematology and Oncology
DO - 10.1186/s13045-026-01851-1
UR - https://hal.science/hal-05805095v1
AB - 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.
SN - 1756-8722
ER -