SLC46A3 as a Potential Predictive Biomarker for Antibody-Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads.

Autor:	Kinneer K; Oncology Research, MedImmune, Gaithersburg, Maryland. kinneerk@medimmune.com., Meekin J; Oncology Research, MedImmune, Gaithersburg, Maryland., Tiberghien AC; Spirogen, QMB Innovation Centre, London, United Kingdom., Tai YT; The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Phipps S; Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, Maryland., Kiefer CM; Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, Maryland., Rebelatto MC; Translational Medicine, MedImmune, Gaithersburg, Maryland., Dimasi N; Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, Maryland., Moriarty A; South Texas Accelerated Research Therapeutics, San Antonio, Texas., Papadopoulos KP; South Texas Accelerated Research Therapeutics, San Antonio, Texas., Sridhar S; Translational Medicine, MedImmune, Gaithersburg, Maryland., Gregson SJ; Spirogen, QMB Innovation Centre, London, United Kingdom., Wick MJ; South Texas Accelerated Research Therapeutics, San Antonio, Texas., Masterson L; Spirogen, QMB Innovation Centre, London, United Kingdom., Anderson KC; The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Herbst R; Oncology Research, MedImmune, Gaithersburg, Maryland., Howard PW; Spirogen, QMB Innovation Centre, London, United Kingdom., Tice DA; Oncology Research, MedImmune, Gaithersburg, Maryland.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Dec 15; Vol. 24 (24), pp. 6570-6582. Date of Electronic Publication: 2018 Aug 21.
DOI:	10.1158/1078-0432.CCR-18-1300
Abstrakt:	Purpose: 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. Experimental Design: 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. 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 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. Conclusions: Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs. (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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