The Role of Specific ATP-Binding Cassette Transporters in the Acquired Resistance to Pyrrolobenzodiazepine Dimer-Containing Antibody-Drug Conjugates.

Abstract

Antibody-drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal phase II trials that contain the payload tesirine, which releases the PBD dimer warhead SG3199. An important consideration in future clinical development is acquired resistance. The aim was to generate and characterize PBD acquired resistant cell lines in both hematologic and solid tumor settings. Human Karpas-299 (ALCL) and NCI-N87 (gastric cancer) cells were incubated with increasing IC50 doses of ADC (targeting CD25 and HER2, respectively) or SG3199 in a pulsed manner until stable acquired resistance was established. The level of resistance achieved was approximately 3,000-fold for ADCT-301 and 3-fold for SG3199 in Karpas-299, and 8-fold for ADCT-502 and 4-fold for SG3199 in NCI-N87. Cross-resistance between ADC and SG3199, and with an alternative PBD-containing ADC or PBD dimer was observed. The acquired resistant lines produced fewer DNA interstrand cross-links, indicating an upstream mechanism of resistance. Loss of antibody binding or internalization was not observed. A human drug transporter PCR Array revealed several genes upregulated in all the resistant cell lines, including ABCG2 and ABCC2, but not ABCB1(MDR1). These findings were confirmed by RT-PCR and Western blot, and inhibitors and siRNA knockdown of ABCG2 and ABCC2 recovered drug sensitivity. These data show that acquired resistance to PBD-ADCs and SG3199 can involve specific ATP-binding cassette drug transporters. This has clinical implications as potential biomarkers of resistance and for the rational design of drug combinations.

• Authors: Simon Corbett, Shiran Huang, Francesca Zammarchi, Philip W Howard, Patrick H van Berkel, John A Hartley
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 9 Pg. 1856-1865 (09 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32669316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ABCC2 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antibodies, Monoclonal, Humanized
• Immunoconjugates
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines
• loncastuximab tesirine

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Antibodies, Monoclonal, Humanized (chemistry, pharmacology)
• Benzodiazepines (chemistry, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoconjugates (chemistry, pharmacology)
• Lymphoma, Large-Cell, Anaplastic (drug therapy, genetics, metabolism)
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Pyrroles (chemistry)
• Stomach Neoplasms (drug therapy, genetics, metabolism)