Immuno-PET detects antibody–drug potency on coadministration with statins Journal Article
| Authors: | Brown, E. L.; Shmuel, S.; Mandleywala, K.; Panikar, S. S.; Berry, N. K.; Rao, Y.; Zidel, A.; Lewis, J. S.; Pereira, P. M. R. |
| Article Title: | Immuno-PET detects antibody–drug potency on coadministration with statins |
| Abstract: | The human epidermal growth factor receptor 2 (HER2)–targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody–drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient–derived xenograft model, we used the 89Zr-labeled or 64Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC. COPYRIGHT ß 2023 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | positron emission tomography; metabolism; epidermal growth factor receptor 2; pathology; cell line, tumor; diagnostic imaging; breast neoplasms; monoclonal antibody; breast tumor; tumor cell line; positron-emission tomography; pet imaging; receptor, erbb-2; trastuzumab; hydroxymethylglutaryl coenzyme a reductase inhibitor; stomach neoplasms; stomach tumor; hydroxymethylglutaryl-coa reductase inhibitors; mevinolin; antibody conjugate; immunoconjugates; trastuzumab emtansine; adc; lovastatin; antibodies, monoclonal, humanized; t-dm1; humans; human; female; ado-trastuzumab emtansine; t-dxd |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 64 |
| Issue: | 10 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2023-10-01 |
| Start Page: | 1638 |
| End Page: | 1646 |
| Language: | English |
| DOI: | 10.2967/jnumed.122.265172 |
| PUBMED: | 37385676 |
| PROVIDER: | scopus |
| PMCID: | PMC10586480 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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