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The study was supported by BBVA Foundation grants for Scientific Research Teams: "Imaging of triple-negative breast cancer with specific miniaturized antibodies by ImmunoPET (BREIMPET) " Ref.:PR [17] _BIO_IMG_0114 (2017) and "Radioinmunotheragnostics for metastatic lung cancer with pretargeted clickable Ab Fragments (TherAbnostic) " Ref.: PR [19] _BIO_IMG_0096. (2020) . This work has also been supported by the Comunidad de Madrid (S2022/BMD-7403 RENIM-CM) .

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Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy☆

Publicated to:NUCLEAR MEDICINE AND BIOLOGY. 136-137 108930- - 2024-06-03 136-137(), DOI: 10.1016/j.nucmedbio.2024.108930

Authors: Magro, Natalia; Oteo, Marta; Romero, Eduardo; Ibanez-Moragues, Marta; Lujan, Victor Manuel; Martinez, Laura; Vela, Oscar; Lopez-Melero, Maria Elena; Arroyo, Alicia G; Garaulet, Guillermo; Martinez-Torrecuadrada, Jorge Luis; Mulero, Francisca; Morcillo, Miguel Angel

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Abstract

Purpose: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumourselective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model. Methods: The LEM2/15 antibody and IgG isotype control were radiolabelled with 89Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [177Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [177Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (gamma H2AX) in MDA 231-BrM2-831 tumours. Results: At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumourto-blood ratio for [89Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15based treatments. A similar uptake was found for [89Zr]Zr-Df-LEM2/15 and [177Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 +/- 1.31 vs. 5.61 +/- 0.66 %ID/g). Tumour doubling time was longer in the [177Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with gamma H2AX-foci was higher in tumours treated with [177Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [177Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4-5 %). Conclusions: The results showed that the 89Zr/177Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.

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