Data from SLC46A3 as a Potential Predictive Biomarker for Antibody–Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads

• DOI: 10.1158/1078-0432.c.6527396.v1
• Publication Date: 2023-04-01T06:25:50Z
• Authors: Krista Kinneer; John Meekin; Arnaud C. Tiberghien; Yu-Tzu Tai; Sandrina Phipps; Christine Mione K...; Marlon C. Rebelatto; Nazzareno Dimasi; Alyssa Moriarty; Kyriakos P. Papad...; Sriram Sridhar; Stephen J. Gregson; Michael J. Wick; Luke Masterson; Kenneth C. Anderson; Ronald Herbst; Philip W. Howard; David A. Tice

<div>AbstractPurpose:<p>Antibody–drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid hematologic malignancies including multiple myeloma. Currently, there no reliable biomarkers of activity these ADCs other than presence the targeted antigen. We observed that certain cell lines innately resistant to such ADCs, sought uncover underlying mechanism resistance.</p>Experimental Design:<p>The expression 43 lysosomal membrane target genes was evaluated bearing linker, pyrrolobenzodiazepine payload SG3376, <i>in vitro</i>. The functional relevance SLC46A3, a transporter ADC catabolites whose uniquely correlated with SG3376 resistance, assessed using EPHA2-, HER2-, BCMA-targeted isogenic cells overexpressing or genetically inactivated <i>SLC46A3</i>. <i>SLC46A3</i> also examined patient-derived xenograft vitro</i> models acquired T-DM1 resistance myeloma bone marrow samples by RT-PCR.</p>Results:<p>Loss found be innate DM1 SG3376. Sensitivity restored refractory upon introduction <i>SLC46A3</i>, suggesting may more predictive antigen levels alone. Interrogation primary indicated range expression, undetectable like BCMA-targeting ADCs.</p>Conclusions:<p>Our findings support as potential patient selection biomarker immediate trials involving ADCs.</p></div>