Abstract
Antibody-drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. 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. The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable 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 multiple myeloma bone marrow samples by RT-PCR. 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 multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs. Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.
Highlights
Antibody–drug conjugates (ADC) combine a mAb with a cytotoxic drug to preferentially eliminate antigen-positive cells for the treatment of cancer [1]
Interrogation of primary multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to B-cell maturation antigen (BCMA)-targeting DM1 and SG3376 ADCs
Four ADCs are approved for clinical use: brentuximab vedotin for the treatment of Hodgkin lymphoma [2], ado-trastuzumab emtansine (T-DM1) for the
Summary
Antibody–drug conjugates (ADC) combine a mAb with a cytotoxic drug (warhead) to preferentially eliminate antigen-positive cells for the treatment of cancer [1]. Upon binding to the targeted antigen on the cell surface, ADCs prepared with enzymatically cleavable linkers (e.g., brentuximab vedotin) or acid-labile hydrazone linkers (e.g., inotuzumab ozogamicin and gemtuzumab ozogamicin) are internalized and processed within the cell, releasing the cytotoxic warhead after linker cleavage. Warheads released in this manner are typically membrane permeable and capable of bystander killing [6,7,8]. Several ADCs utilizing noncleavable linkers are currently in clinical development and target both solid tumors and hematologic malignancies, including diffuse large Bcell lymphoma and multiple myeloma (refs. 13–16)
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