Abstract 4601: Development and clinical translation of a phage display derived MT1-MMP-specific bicyclic peptide for radiotheranostic applications

Background: Membrane type 1 matrix metalloproteinase (MT1-MMP) is a pivotal enzyme involved in extracellular matrix remodeling, contributing to tumor invasion, metastasis, and poor prognosis in various cancers, including non-small cell lung, urothelial, pancreatic, gastric, and breast cancers. This study outlines the preclinical development and first in-human application of a phage display-derived MT1-MMP-specific bicyclic peptide, [68Ga]Ga-BCY25286, as a radiotheranostic agent for PET/CT imaging. Methods: The MT1-MMP-targeting bicyclic peptide BCY25286 was radiolabeled with either Ga-68 or Lu-177 and subsequently characterized for stability, binding affinity, and internalization. Preclinical evaluation included biodistribution and μPET/MR imaging in MT1-MMP+ HT1080 and MT1-MMP- MCF-7 xenograft tumor-bearing nude mice. For clinical translation, a 65-year-old patient with advanced pulmonary adenocarcinoma underwent [18F]FDG-PET/CT followed by [68Ga]Ga-BCY25286 PET/CT imaging, with PET scans performed after 60 minutes for [18F]FDG and up to 60 minutes for [68Ga]Ga-BCY25286 (compassionate use). Results: Radiolabeling achieved >99% radiochemical purity for both radionuclides. [68Ga]Ga-BCY25286 demonstrated highly MT1-MMP-specific binding (7.2 ± 1.6 nM), proteolytic stability up to 72 hours, and rapid background clearance, thereby enhancing imaging contrast within 30 minutes. In mice, the tracer demonstrated high tumor uptake (10.6 ± 1.1 %ID/g at 1 h p.i.) with persistence up to 24 hours. In the clinical case, [68Ga]Ga-BCY25286 PET/CT imaging revealed high uptake in both primary and biopsy-confirmed metastatic sites, corroborating the findings of [18F]FDG-PET. SUVmaxvalues were comparable for lymph node metastases but higher for bone metastases in MT1-MMP-PET compared to [18F]FDG-PET, with significant kidney retention due to renal excretion. Conclusion: This first-in-human application of MT1-MMP-targeting [68Ga]Ga-BCY25286 demonstrates the feasibility for visualization of MT-1-MMP-expressing primary tumors and metastases, which is in line with the preclinical findings. These initial clinical results support further investigation of [68Ga]Ga-BCY25286 as a diagnostic tool with potential to improve tumor characterization and patient management strategies in MT1-MMP-positive cancers. Citation Format: Ann-Christin Eder, Mohamed A. Omrane, Anusha R. Regupathy, Mohamed El Fakiri, Nils Steinacker, Lisa-Charlotte Domogalla, Christoph-Ferdinand Wielenberg, Michael Mix, Johanna Lahdenranta, Ben Blakeman, Francesca Wood, Philip Huxley, Gemma E. Mudd, Matthias Eder, Philipp T. Meyer, Martin T. Freitag. Development and clinical translation of a phage display derived MT1-MMP-specific bicyclic peptide for radiotheranostic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4601.