Abstract Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy with no FDA-approved systemic therapies and limited benefit from conventional treatments. Proteogenomic profiling has revealed consistent overexpression of AXL, providing a compelling rationale to pursue AXL as a novel therapeutic target. We investigated mipasetamab uzoptirine (ADCT-601), an AXL-targeting antibody-drug conjugate (ADC) with pyrrolobenzodiazepine dimer payload, in preclinical models of ACC. In vitro cytotoxicity was assessed in AXL-positive cell lines, and in vivo efficacy was evaluated using cell line xenograft and patient-derived xenograft (PDX) models. ADCT-601 demonstrated potent and selective cytotoxicity in AXL-expressing ACC cell lines. In xenograft models, a single administration at 0.5 or 1.0 mg/kg induced significant tumor regression, with complete tumor eradication observed at 1.0 mg/kg. Across a panel of ACC PDX models, ADCT-601 produced strong yet variable anti-tumor activity, with therapeutic response correlating with AXL expression levels. ADCT-601 demonstrates robust AXL expression linked to anti-tumor activity in preclinical models of ACC, establishing a proof-of-concept for targeting AXL in this rare cancer. These findings support clinical translation of AXL-targeting ADC as a novel biomarker-driven therapy for patients in ACC.
Humtsoe et al. (Tue,) studied this question.
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