SLC46A3 as a potential predictive biomarker for antibody-drug conjugates bearing non-cleavable linked maytansinoid and pyrrolobenzodiazepine warheads

Purpose: Antibody-drug conjugates (ADCs) utilizing non-cleavable linker-drugs have been approved for clinical use, and several are in development targeting solid and hematological malignancies including multiple myeloma (MM). Currently there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance. Experimental Design: The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the non-cleavable linker pyrrolobenzodiazepine payload SG3376 in vitro. The functional relevance of SLC46A3, a lysosomal transporter of non-cleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EphA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in-vitro models of acquired T-DM1 resistance and MM bone marrow samples by RT-PCR. Results: Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary MM samples indicated a range of SLC46A3 expression, including samples with undetectable levels like MM cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs. Conclusion: Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.

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