PET imaging of microglia in Alzheimer's disease using copper-64 labeled TREM2 antibodies.

in Theranostics by Monireh Shojaei, Rebecca Schaefer, Kai Schlepckow, Lea H Kunze, Felix L Struebing, Bettina Brunner, Michael Willem, Laura M Bartos, Astrid Feiten, Giovanna Palumbo, Thomas Arzberger, Peter Bartenstein, Gian Carlo Parico, Dan Xia, Kathryn M Monroe, Christian Haass, Matthias Brendel, Simon Lindner

TLDR

  • The study aims to develop a tool to measure a protein called TREM2 in the brain. The study uses a special kind of radiation called PET (Positron Emission Tomography) to track the protein in the brain. The study also uses a special kind of antibody to help the PET track the protein better. The study tests the effectiveness of the tool and finds that it can accurately measure TREM2 in the brain. The study also finds that the tool can be used to measure TREM2 in people with Alzheimer's disease and other brain diseases. The study suggests that the tool could be used to help doctors diagnose and treat these diseases.

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in microglia activation and is being investigated as a potential therapeutic target for modulation of microglia in several neurological diseases. In this study, we present the development and preclinical evaluation ofCu-labeled antibody-based PET radiotracers as tools for non-invasive assessment of TREM2 expression. Furthermore, we tested the potential of an antibody transport vehicle (ATV) that binds human transferrin receptor to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement.A TREM2 antibody with an engineered transport vehicle (ATV:4D9) and without (4D9) were covalently modified withNCS-benzyl-NODAGA and labeled with copper-64. Potency, stability, and specificity were assessedfollowed byPET imaging at the early 2 h, intermediate 20 h, and late imaging time points 40 h post-injection using a human transferrin receptor (hTfR) expressing model for amyloidogenesis (5xFAD;TfR) or wild-type mice (WT;TfR), and hTfR negative controls. Organs of interest were isolated to determine biodistribution byautoradiography. Cell sorting aftertracer injection was used to demonstrate cellular specificity for microglia and to validate TREM2 PET results in an independent mouse model for amyloidogenesis (App;TfR). For translation to human imaging, a human TREM2 antibody (14D3) was radiolabeled and used forautoradiography on human brain sections.TheCu-labeled antibodies were obtained in high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity. Antibody modification did not impact TREM2 binding. ATV:4D9 binding proved to be specific, and the tracer stability was maintained over 48 h. The uptake of [Cu]Cu-NODAGA-ATV:4D9 in the brains of hTfR expressing mice was up to 4.6-fold higher than [Cu]Cu-NODAGA-4D9 in mice without hTfR. TREM2 PET revealed elevated uptake in the cortex of 5xFAD mice compared to wild-type, which was validated by autoradiography. PET-to-biodistribution correlation revealed that elevated radiotracer uptake in brains of 5xFAD;TfRmice was driven by microglia-rich cortical and hippocampal brain regions. Radiolabeled ATV:4D9 was selectively enriched in microglia and cellular uptake explained PET signal enhancement in App;TfRmice. Human autoradiography showed elevated TREM2 tracer binding in the cortex of patients with Alzheimer's disease.[Cu]Cu-NODAGA-ATV:4D9 has potential for non-invasive assessment of TREM2 as a surrogate marker for microglia activation. ATV engineering for hTfR binding and transcytosis overcomes the blood-brain barrier restriction for antibody-based PET radiotracers. TREM2 PET might be a versatile tool for many applications beyond Alzheimer's disease, such as glioma and chronic inflammatory diseases.

Overview

  • The study aims to develop and evaluate Cu-labeled antibody-based PET radiotracers for non-invasive assessment of TREM2 expression in the brain. The study uses an antibody transport vehicle (ATV) to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement. The study evaluates the potential of an antibody transport vehicle (ATV:4D9) that binds human transferrin receptor to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement. The study also evaluates the potential of a human TREM2 antibody (14D3) for autoradiography on human brain sections. The study uses a human transferrin receptor (hTfR) expressing model for amyloidogenesis (5xFAD;TfR) or wild-type mice (WT;TfR), and hTfR negative controls to test the potential of the radiotracers. The study also uses an independent mouse model for amyloidogenesis (App;TfR) to validate the results. The study aims to develop a versatile tool for many applications beyond Alzheimer's disease, such as glioma and chronic inflammatory diseases.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies significant differences in the results between the conditions. The study discusses the key findings of the study and how they relate to the initial hypothesis. The study shows that the Cu-labeled antibody-based PET radiotracers were obtained in high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity. The study shows that antibody modification did not impact TREM2 binding. The study shows that the uptake of [Cu]Cu-NODAGA-ATV:4D9 in the brains of hTfR expressing mice was up to 4.6-fold higher than [Cu]Cu-NODAGA-4D9 in mice without hTfR. The study shows that TREM2 PET revealed elevated uptake in the cortex of 5xFAD mice compared to wild-type, which was validated by autoradiography. The study shows that PET-to-biodistribution correlation revealed that elevated radiotracer uptake in brains of 5xFAD;TfR mice was driven by microglia-rich cortical and hippocampal brain regions. The study shows that radiolabeled ATV:4D9 was selectively enriched in microglia and cellular uptake explained PET signal enhancement in App;TfR mice. The study shows that human autoradiography showed elevated TREM2 tracer binding in the cortex of patients with Alzheimer's disease.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice. The study identifies limitations of the study that need to be addressed in future research. The study suggests possible future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. The study shows that the Cu-labeled antibody-based PET radiotracers have potential for non-invasive assessment of TREM2 as a surrogate marker for microglia activation. The study shows that ATV engineering for hTfR binding and transcytosis overcomes the blood-brain barrier restriction for antibody-based PET radiotracers. The study shows that TREM2 PET might be a versatile tool for many applications beyond Alzheimer's disease, such as glioma and chronic inflammatory diseases.
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