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

• Published in: Nuclear medicine and biology Vol. 136-137; p. 108930
• Main Authors: Magro, Natalia, Oteo, Marta, Romero, Eduardo, Ibáñez-Moragues, Marta, Lujan, Victor Manuel, Martínez, Laura, Vela, Oscar, López-Melero, Maria Elena, Arroyo, Alicia G., Garaulet, Guillermo, Martínez-Torrecuadrada, Jorge Luis, Mulero, Francisca, Morcillo, Miguel Angel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2024
• Subjects: Animals; Antibody-target engagement; Beta Particles - therapeutic use; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Humans; Lutetium; Matrix Metalloproteinase 14 - metabolism; Mice; MT1-MMP; Patlak linearisation; Positron-Emission Tomography - methods; Radioisotopes; Theranostics; Tissue Distribution; Triple Negative Breast Neoplasms - diagnostic imaging; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy; Triple-negative breast cancer; Zirconium - chemistry; Patlak linearisation; MT1-MMP; Antibody-target engagement; Theranostics; Triple-negative breast cancer
• ISSN: 0969-8051; 1872-9614; 1872-9614
• DOI: 10.1016/j.nucmedbio.2024.108930

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 tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model.
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.
At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-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 %).
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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