@misc{10481/98144,
year = {2024},
month = {6},
url = {https://hdl.handle.net/10481/98144},
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 (γH2AX) 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 LEM2/15-
based 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 γH2AX-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.},
organization = {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)},
organization = {Comunidad de Madrid (S2022/BMD-7403 RENIM-CM)},
publisher = {Elsevier},
keywords = {Triple-negative breast cancer},
keywords = {Antibody-target engagement},
keywords = {MT1-MMP},
title = {Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy☆},
doi = {10.1016/j.nucmedbio.2024.108930},
author = {Magro, Natalia and Oteo, Marta and Romero Sanz, Eduardo and Ibáñez Moragues, Marta and Manuel Lujan, Victor and Martínez, Laura and Vela, Oscar and López Melero, María Elena and Arroyo, Alicia G. and Garaulet, Guillermo and Martínez Torrecuadrada, Jorge Luis and Mulero, Francisca and Morcillo, Miguel Ángel},
}