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

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 tumour-selective 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 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 %).

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.

Keywords: Antibody-target engagement; MT1-MMP; Patlak linearisation; Theranostics; Triple-negative breast cancer.