Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy☆ Magro, Natalia Oteo, Marta Romero Sanz, Eduardo Ibáñez Moragues, Marta Manuel Lujan, Victor Martínez, Laura Vela, Oscar López Melero, María Elena Arroyo, Alicia G. Garaulet, Guillermo Martínez Torrecuadrada, Jorge Luis Mulero, Francisca Morcillo, Miguel Ángel Triple-negative breast cancer Antibody-target engagement MT1-MMP 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. 2024-12-17T12:47:38Z 2024-12-17T12:47:38Z 2024-06-03 journal article Magro, N. et. al. Nuclear Medicine and Biology 136-137 (2024) 108930. [https://doi.org/10.1016/j.nucmedbio.2024.108930] https://hdl.handle.net/10481/98144 10.1016/j.nucmedbio.2024.108930 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier